Ru- and Pd-catalysed synthesis of 2-arylfurans by one-flask heck arylation/oxidation

Article abstract of DOI:10.1002/ejoc.201100549

2,5-Disubstituted furans were synthesized by one-flask Heck arylation/oxidation sequences. The starting materials are 2-substituted 2,3-dihydrofurans, conveniently available by RCM/isomerization sequences, and arenediazonium salts. These react in ligand-free Heck reactions to afford 2,5-disubstituted 2,5-dihydrofurans, which are oxidized to the corresponding furans without isolation or intermediate workup. The oxidation is conveniently achieved with chloranil or DDQ, depending on the substrate.

Full text of DOI:10.1002/ejoc.201100549

FULL PAPER
DOI: 10.1002/ejoc.201100549
Ru- and Pd-Catalysed Synthesis of 2-Arylfurans by One-Flask Heck
Arylation/Oxidation
Bernd Schmidt*[a] and Diana Geißler[a]
Keywords: Diazonium salts / Palladium / C–C coupling / Heck coupling / Furans / Oxidation / Oxygen heterocycles
2,5-Disubstituted furans were synthesized by one-flask Heck
arylation/oxidation sequences. The starting materials are 2-
substituted 2,3-dihydrofurans, conveniently available by
RCM/isomerization sequences, and arenediazonium salts.
These react in ligand-free Heck reactions to afford 2,5-disub-
stituted 2,5-dihydrofurans, which are oxidized to the corre-
sponding furans without isolation or intermediate workup.
The oxidation is conveniently achieved with chloranil or
DDQ, depending on the substrate.
Introduction
2-Substituted and 2,5-disubstituted furans are important
substructures of several drugs currently in clinical use.[1]
Some of these, such as the diuretic furosemide (1, Figure 1)
or the peptic ulcer therapeutic ranitidine (2), are best syn-
thesized from cheap and conveniently available furans such
as furan-2-carbaldehyde, furfuryl alcohol or furfurylamine,
with use of electrophilic Mannich-type alkylation reac-
tions[2] for the introduction of their second side chains. For
the synthesis of 2-arylfurans different methods are required.
The muscle relaxant dantrolene (3), commonly used for the
treatment of life-threatening complications during anaes-
thesia,[3] for instance, has been synthesized from furfural
and an arenediazonium salt[4] through a Cu-catalysed
Meerwein arylation.[5] Formation of the quinazoline–furan
C–C bond in the anticancer agent lapatinib (4), a tyrosine
kinase inhibitor, was achieved through a Suzuki–Miyaura
coupling between a 2-furylboronic acid and an appropri-
ately substituted quinazolinyl iodide (Figure 1).[6]
Figure 1. Approved drugs containing furan substructures.
Apart from these clinically approved drugs, numerous
other 2-aryl-, 2-alkyl-5-aryl- and 2,5-diarylfurans have been
investigated as drug candidates in medicinal chemistry stud-
ies over the past decade. These compounds (Figure 2) were
tested for diverse applications, such as activity against sev-
eral cancer cell lines (compounds 5 and 6),[7] cardioprotec-
tive activity through inhibition of Na+/H+ exchangers
(7),[8,9] activity as an HIV-integrase inhibitor (8),[10,11] ac-
tivity against Mycobacterium tuberculosis (9)[12] or as poten-
tial therapeutics for smoking cessation (10).[13]
Figure 2. Examples of drug candidates containing arylfuran moie-
ties.
[a] Universität Potsdam, Institut für Chemie (Organische
Synthesechemie),
Because of the low to moderate yields normally observed
for Meerwein arylation reactions of furans, this method is
restricted to cheap or conveniently available starting materi-
als. For certain substrates, the TiIII-mediated arylation of
furans with diazonium salts might have potential as a useful
alternative.[14] It has been reported, though, that Meerwein-
Karl-Liebknecht-Straße 24–25, Haus 25, 14476 Golm,
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.201100549.
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Ru- and Pd-Catalysed One-Flask Synthesis of 2-Arylfurans
type arylation reactions cannot be applied to the synthesis hydrogenation step appeared advantageous.[32] Alterna-
of 2,5-diarylfurans such as 6 or 9,[7] which have instead been tively, a one-flask RCM/oxidation sequence that uses stoi-
synthesized from symmetrical 2,5-distannylfurans[15] in chiometric amounts of benzoquinones as oxidants has been
double Stille couplings. The disadvantages of this method developed for the same transformation.[33] In the furan
include potential contamination of the products with or- series, we are aware of one example of such a sequence.[34]
ganostannane residues, as well as selectivity issues arising Benzoquinones – DDQ in particular – have also been used
when the method is adopted for the synthesis of unsymmet- in a few cases for the oxidation of 2,5-disubstituted 2,5-
rical 2,5-diarylfurans. To overcome these drawbacks we dihydrofurans to the corresponding furans.[35–37] Spontane-
sought an alternative route not based on furan cross-cou- ous oxidation of 2,5-dihydrofurans by air[38] and their de-
pling reactions. Inspired by recent research in our group hydrogenation catalysed by Pd/C[39] appear to be less gene-
directed towards the synthesis of centrolobines[16] and re- ral and therefore only of limited use.
lated diarylheptanoids[17] through Heck coupling reactions
Inspired by a protocol developed by Cossy and Belotti
of dihydropyrans and arenediazonium salts,[18] we decided for the Pd/C-catalysed aromatisation of enamines to anil-
to investigate the feasibility of a synthesis as outlined in ines,[40] we tested nitrobenzene as a hydrogen acceptor in
Scheme 1.
the Ru-catalysed RCM of the diallyl ether 11b (Scheme 2).
Under these conditions, only the expected RCM product
16b was observed, but no furan 17b. However, application
of Cossy’s conditions to 16b indeed resulted in the forma-
tion of the desired furan with 75% conversion and good
selectivity. Unfortunately, though, separation of the product
from unreacted nitrobenzene turned out to be very difficult,
resulting in a reduced yield of only 20%. We then examined
Shvo’s catalyst (B)[41] for the dehydrogenation of the dihy-
drofuran 16b, using acetone as a solvent and hydrogen ac-
ceptor. Although it had previously been demonstrated that
this catalyst is efficient for the dehydrogenation of second-
ary alcohols,[42] to the best of our knowledge it has not been
used for dehydrogenative aromatization reactions.[43] Upon
treatment of 16b with Shvo’s catalyst (B) in acetone, we
were indeed able to isolate the furan 17b from the reaction
mixture in 4% yield, along with an 11% yield of the satu-
rated ketone 18b and a 53% yield of the α,β-unsaturated
ketone 19b (Scheme 2).
Scheme 1. RCM/Heck reaction/oxidation approach to furans.
Accordingly, the diallyl ethers 11, conveniently available
with a variety of R substituents, were envisaged as starting
materials. Subjection of these diallyl ethers to an RCM/
isomerization sequence[19–22] should yield the 2-substituted
2,3-dihydrofurans 12, which should react with the arenedi-
azonium salts 13 under Pd-catalysis conditions[23–25] to af-
ford the 2,5-disubstituted 2,5-dihydrofurans 14.[18] Oxi-
dation or dehydrogenation of these intermediates should
give the desired 2,5-disubstituted furans 15. Similarly, the
2-substituted furans 17 should be obtainable from the same
precursors 11 through RCM and subsequent oxidation/de-
hydrogenation of the intermediate 2-substituted 2,5-dihy-
drofurans 16. For synthetic purposes, it should be most
convenient to combine the transition-metal-catalyzed step
and the aromatization step in a one-flask sequence, and we
therefore decided to investigate this option.
Results and Discussion
Assisted tandem[26] RCM/aromatization sequences,[27,28]
characterized by the use of a single Ru precatalyst that un-
dergoes an organometallic conversion to a dehydrogenation
catalyst in situ, are scarce.[29–31] In most cases the heteroaro-
matic product is obtained in minor quantities as a side
product, or the reaction is not general and difficult to re-
produce. In this respect, an orthogonal tandem catalytic se-
quence originally developed for the synthesis of pyrroles
Scheme 2. Unsuccessful dehydrogenation experiments.
The mechanism proposed in Scheme 3 would explain the
from diallylamines through the use of Ru–carbenes for the formation of all three products 17b, 18b and 19b. Initially,
metathesis step and RuCl3 to promote the subsequent de- the catalyst B might dissociate into the reducing species BЈ
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B. Schmidt, D. Geißler
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Scheme 3. Proposed mechanism for the ring cleavage of dihydrofurans.
and the oxidizing species BЈЈ.[41] We assume that the former (Scheme 4). This substrate was synthesized from 12a and
is responsible for the preferred pathway, leading to the 13a by means of a Heck reaction[18] and, after purification,
ketone 19b. Presumably, the dihydrofuran 16b could coordi- was treated with Shvo’s catalyst in acetone at reflux. To-
nate to the Ru atom through the ring oxygen atom, giving gether with recovery of the starting material 14aa (46%),
the complex CЈ. This could undergo insertion of the steri- we isolated the enone 19a (27%) and the desired 2,5-disub-
cally less hindered C–O bond into the Ru–H bond (Ru– stituted furan 15aa in 11% yield. Unlike in the analogous
alkoxide DЈ), followed by β-hydride elimination to give EЈ. reaction of the monosubstituted dihydrofuran 16b, no satu-
The two following steps could result in an isomerization rated ketone 18a, resulting from hydrogen transfer to the
of the initially formed (Z)-enone to the thermodynamically ring-opening product 19a, was observed. Presumably, ace-
more stable (E)-enone. This isomerization might involve a tone is a better hydrogen acceptor than 19a in this case.
migratory insertion, giving the Ru–enolate FЈ, and a final
β-hydride elimination to afford (E)-19b and the catalytically
active species BЈ. An important clue for understanding the
formation of 17b and 18b was provided by examination of
1
the H NMR spectra of the crude reaction mixture. These
products are present in a ratio of approximately 1:1, sug-
gesting that their formation is not independent, but that 19b
serves as a hydrogen acceptor for the starting material 16b,
which is simultaneously dehydrogenated to afford the furan
17b. We propose a mechanism involving coordination of the
dihydrofuran 16b to the oxidizing Ru species BЈЈ, probably
through the C–C double bond. Migration of a proton in
the η2-alkene complex CЈЈ to the carbonyl group of the cy-
clopentadienone ligand could give the η3-allyl–Ru complex
DЈЈ, which could undergo β-hydride elimination to afford
the furan 17b and the reducing catalyst BЈ. Regeneration of
the oxidizing catalyst BЈЈ could occur either through hydro-
Scheme 4. Ring-opening versus dehydrogenation reactions of the
2,5-disubstituted dihydrofuran 14aa catalysed by Shvo’s catalyst.
genation of the enone 19b to afford the ketone 18b, as out-
In view of these rather unsatisfactory results, we investi-
lined in Scheme 3, or through hydrogenation of the acetone gated the potential of one-flask sequences consisting of a
solvent (not shown). Because 17b and 18b are formed in transition-metal-catalysed step and a benzoquinone-medi-
equimolar amounts, it appears likely that the enone 19b is ated oxidation step. To this end, the metathesis precursors
a much better hydrogen acceptor than acetone, which is 11a and 11b (Table 1) were treated with first-generation
present in a large excess.
Grubbs catalyst (A) at slightly elevated temperature, and
A similar result was observed for the attempted aromati- after completion of the RCM step the oxidant was added,
zation of the 2,5-disubstituted dihydrofuran 14aa without intermediate purification or exchange of solvents.
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Ru- and Pd-Catalysed One-Flask Synthesis of 2-Arylfurans
Table 1. One-flask RCM/oxidation.
Table 2. Synthesis of the 2-substituted 2,3-dihydrofurans 12 used in
this study.
Entry
11
R
Oxidant
[equiv.]
Ratio of
Product
(yield)
16/17[a]
Entry Starting
material
R
Product Yield
Ref.
1
2
3
4
11a PhCH2CH2 CA[b] (1.2) Ͼ19:1
11a PhCH2CH2 DDQ (1.2) 1:3.5
n.d.
n.d.
17a (51%)
17b (61%)
[22]
1
2
3
4
11a
11b
11c
11d
PhCH2CH2
4-MeOC6H4
Ph
12a
12b
12c
12d
68%
this work
this work
this work
11a PhCH2CH2 DDQ (2.0) Ͻ1:19
11b 4-MeOC6H4 CA[b] (1.2) Ͻ1:19
60%
59%
BnOCH2
1
[a] Ratios were determined by H NMR spectroscopy of the crude
reaction mixture. [b] CA = chloranil.
An important result of these experiments is the finding
that chloranil (CA)[44] cannot be used for the one-flask con-
version of the alkyl-substituted diallyl ether 11a into the
corresponding furan 17a. Instead, the intermediate RCM
product 16a was isolated quantitatively (Table 1, Entry 1).
With DDQ[45] (1.2 equiv.) under otherwise identical condi-
tions, approximately 75% conversion to the desired furan
17a was observed (Entry 2). With an increase in the amount
of DDQ to 2.0 equiv. the reaction went to completion, and
17a was isolated in 51% yield (Entry 3). In the case of the
4-methoxyphenyl-substituted diallyl ether 11b the oxidation
step proceeded much more smoothly: for this substrate
1.2 equiv. of chloranil was sufficient to achieve quantitative
oxidation to the furan 17b (Entry 4). Oku et al. showed by
measurement of the redox potentials in acetonitrile that
DDQ is a significantly stronger oxidant than chloranil,[46]
which is consistent with these results.
We next investigated the synthesis of the various 2,5-di-
substituted furans 15 by a one-flask Heck arylation/oxi-
dation sequence as outlined in Scheme 1. The starting mate-
rials required for this route – the 2-substituted 2,3-dihy-
drofurans 12 – were synthesized from the diallyl ethers 11
by the tandem RCM/isomerization sequence. As we have
previously reported, ethyl vinyl ether is the best additive for
this particular ring size, because competing transfer hydro-
genation[47] is excluded.[22] The diallyl ethers 11a–d were
thus treated with the first-generation Grubbs catalyst A. Af-
ter completion of the RCM step, ethyl vinyl ether was
added, and the reaction mixture was heated to reflux. Un-
der these conditions, the propagating species of the metath-
esis reaction is converted into a rutheium hydride, as de-
scribed previously by Louie and Grubbs,[48] which catalyses
the double-bond migration (Table 2).
Figure 3. Arenediazonium salts used for the one-flask Heck aryl-
ation/oxidation sequence.
Previous investigations into Heck reactions with arenedi-
azonium salts had found acetonitrile to be the best solvent
for arylations of cyclic enol ethers[18] and enamides.[51]
Methanol, although commonly used for Pd-catalysed cou-
pling reactions of diazonium salts and electron-deficient al-
kenes, is less suitable for these substrates, because compet-
ing acetal formation poses a major problem.[52] For these
reasons, the previously optimized conditions for intermo-
lecular Heck arylations of cyclic enol ethers, as described in
Scheme 4 for the synthesis of 14aa, were adopted for the
envisaged one-flask sequences. The Pd-catalysed coupling
reactions are normally fast, and their completion is easily
recognized when the evolution of nitrogen ceases. After-
wards, the appropriate oxidants were added, and the reac-
tion mixtures were heated at 80 °C for 20 h (Scheme 5). The
results are listed in Table 3: remarkably, even the Heck cou-
pling products resulting from the 2-alkyl-substituted 2,3-di-
hydrofuran 12a underwent oxidation to the corresponding
furans 15aa–15ae smoothly in the presence of the milder
oxidant chloranil, whereas DDQ was required for the oxi-
dation of the dihydrofuran 16a, without an aromatic sub-
stituent directly attached to the heterocycle. In those cases
in which the conversion was incomplete with 1.2 equiv. of
oxidant (Entries 2, 4, 5 and 8) the remaining amount of
The diazonium salts 13a–e were tested as coupling part-
ners. Compounds 13a–c and 13e were synthesized from the
corresponding acetanilides. As we have described pre-
viously, the required diazonium salts were obtained in
higher purities by this route, which has been found to be
beneficial for their application in Pd-catalysed coupling re-
actions.[49] The trimethoxy-substituted diazonium salt 13d
could be synthesized from the corresponding aniline by a
literature procedure (Figure 3).[50]
Scheme 5. One-flask Heck arylation/oxidation sequence. See
Table 3 for results.
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B. Schmidt, D. Geißler
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Table 3. One-flask Heck arylation/oxidation sequence for the synthesis of the 2,5-disubstituted furans 15 (see Scheme 5 for reaction
details).
[a] Refers to conversion of the oxidation step. Determined by 1H NMR spectroscopy of the crude reactions mixture. [b] Reaction mixtures
consist only of the furan 15 and the Heck arylation product 14. [c] Compounds 15bb and 15ca are identical. Different notations are used
to distinguish between the two different approaches to their synthesis. [d] Complex mixture of products was observed by 1H NMR
spectroscopy.
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Ru- and Pd-Catalysed One-Flask Synthesis of 2-Arylfurans
material is the unreacted dihydrofuran 14. With an increase (Entries 27/28 and 30/31), preparatively useful yields of the
in the amount of oxidant to 2.0–3.7 equiv., full conversion furans 15dc and 15de were isolated. Notably, the rate of
into the corresponding furans 15ab, 15ac and 15ae was conversion can be improved only to a very limited extent
achieved (Entries 3, 6 and 9).
by increasing the amount of oxidant: in the case of the fur-
Very similar reactivity was observed for the 2-phenyl- an 15de; for instance, 77% conversion was obtained with
substituted derivatives (Table 3, Entries 15–22). Again, 1.2 equiv. of DDQ, resulting in a yield of 65%, whereas
Heck coupling products of electron-rich arenediazonium with 2.5 equiv. of DDQ full conversion was observed, but
salts (Entries 15, 16, 20) were smoothly oxidized to the cor- the isolated yield was lower than 5%, due to extensive de-
responding furans 15ca, 15cb and 15cd with 1.2 equiv. of composition.
chloranil, whereas larger amounts of the oxidant were re-
The more facile oxidation of substrates bearing electron-
quired for 15cc and 15ce (Entries 17–19 and 21–22). It is in rich aromatic substituents is most probably a consequence
line with these observations that 1.2 equiv. of chloranil are of their higher HOMO energies. In these cases, slight ex-
sufficient for quantitative oxidation of all Heck coupling cesses of chloranil are sufficient to oxidize the aromatic sys-
products derived from the p-methoxyphenyl-substituted tems to the radical cations 20 (Scheme 7), which are depro-
2,3-dihydrofuran 12b (Table 3, Entries 10–14). Rather dis- tonated to afford the radicals 21. These are in turn oxidized
appointing results were obtained for most derivatives to the stabilized carbenium ions 22. Second deprotonations
bearing benzyloxymethyl substituents at their 2-positions yield the furans 15 (R = Ar) or 17b (R = H).
(Entries 23–31). Admittedly, these transformations should
be quite challenging, in view of the well-documented sensi-
tivity of benzyl protecting groups towards oxidizing agents
such as DDQ.[53] In a first experiment, 12d and the di-
azonium salt 13a were subjected to the standard conditions,
with chloranil (1.2 equiv.) as the oxidant. Under these con-
ditions, the intermediate Heck arylation product, the di-
hydrofuran 14da, was fully consumed, but a complex mix-
1
ture of products was observed in the H NMR spectrum of
the crude reaction mixture. After replacement of chloranil
with DDQ, the desired furan 15da was detected in small
Scheme 7. Sequential oxidation/deprotonation mechanism for aryl-
substituted derivatives.
amounts in the crude mixture, but it could be isolated only
in yields below 5%. This particularly difficult example was
therefore investigated in some detail, by conducting the two
steps separately (Scheme 6).
Dihydrofurans bearing either phenyl substituents or aro-
matic substituents with electron-withdrawing groups are
less prone to oxidation. It might be that in these cases the
oxidations proceed through removal of single electrons
from the C–C double bonds, which should require a
stronger oxidant. This might explain why DDQ is required
for the one-flask conversion of the diallyl ether 11a into the
corresponding furan 17a (Table 1): presumably, the RCM
product 16a (Scheme 8) is first oxidized to the radical cat-
ion 23, which undergoes deprotonation to give the allyl rad-
ical 24. This radical is then oxidized to the carbocation 25,
and final deprotonation gives the furan 17a.
Scheme 6. Two-step synthesis of 15da.
The reaction between 12d and 13a under the standard
conditions established for this transformation afforded the
intermediate 14da only in 22% yield. NMR spectroscopy of
the crude reaction mixture revealed that the Pd-catalysed
step proceeded somewhat sluggishly, with the formation of
small amounts of unidentified byproducts. In particular, a
notable amount of the cis diastereomer, not normally ob-
served under these coupling reactions, was detected. A
thoroughly purified 3:1 mixture of trans/cis-14da was then
treated with DDQ (1.2 equiv.) in toluene. Under these con-
ditions, the furan 15da was isolated in 48% yield.
Scheme 8. Sequential oxidation/deprotonation mechanism for
alkyl-substituted derivatives.
Similarly, very low isolated yields of the desired furans
15db and 15dd were obtained by the one-flask protocol.
However, in those cases in which an electron-deficient aro-
Conclusions
We have established a one-flask method for the synthesis
matic substituent was introduced in the Heck arylation step of furans, ultimately starting from simple diallyl ethers. The
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B. Schmidt, D. Geißler
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then heated at 80 °C for 20 h. After completion of the reaction, the
mixture was quenched by addition of saturated aqueous NaHCO3
solution. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3ϫ20 mL). The combined or-
ganic extracts were washed with saturated aqueous NaHCO3 solu-
tion and brine, dried with MgSO4 and filtered, and the solvents
were evaporated. The residue was purified by column chromatog-
raphy on silica gel with hexane/MTBE mixtures as eluents to give
the desired furans 15.
sequence consists of transition-metal-catalysed C–C bond-
forming reactions, such as RCM and the Heck reaction,
and subsequent oxidative aromatization through the use
either of chloranil or of DDQ. In particular, our method
is well suited for the synthesis of 2,5-disubstituted furans,
including unsymmetrical 2,5-diaryl furans, which play an
increasingly important role in medicinal chemistry and drug
discovery.
2-(4-Methoxyphenyl)-5-phenethylfuran (15aa): This compound was
obtained by the General Procedure, from 12a (227 mg, 1.3 mmol),
the diazonium salt 13a (289 mg, 1.0 mmol) and chloranil (397 mg,
1.6 mmol, 1.2 equiv.). The crude product was purified by column
chromatography on silica gel with a mixture of hexane/MTBE
(20:1) as eluent. Yield of 15aa: 163 mg (0.6 mmol, 45%), m.p. 75–
Experimental Section
General Remarks: All experiments were conducted in dry reaction
vessels under dry nitrogen. Solvents were purified by standard pro-
1
1
cedures. H NMR spectra were obtained with a Bruker DRX 300
78 °C. H NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 8.9 Hz, 2 H,
spectrometer at 300 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) as
an internal standard. Coupling constants (J) are given in Hz. Signal
assignments refer to 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 an internal standard. IR spectra were recorded with
a Nicolet Impact 400 D instrument as films on NaCl or KBr plates
4-H), 7.37–7.18 (5 H, Ph), 6.93 (d, J = 8.9 Hz, 2 H, 3-H), 6.41 (d,
J = 3.2 Hz, 1 H, 7-H/8-H), 6.04 (d, J = 3.2 Hz, 1 H, 8-H/7-H), 3.84
(s, 3 H, 1-H), 2.98–3.07 (4 H, 10-H, 11-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.7, 154.4, 152.4, 141.2, 128.4, 128.3,
126.0, 124.8, 124.4, 114.1, 107.3, 104.0, 55.3, 34.5, 30.1 ppm. IR
(KBr disc): ν = 1717, 1600, 1578, 1553, 1498, 1454, 1294, 1248,
˜
1174, 1110, 1029, 831, 781, 750, 698 cm–1. LRMS (EI): m/z (%) =
91 (26), 115 (13), 135 (22), 144 (18), 187 (100), 188 (13), 278 (13)
[M]+. HRMS (EI): calcd. for C19H18O2 [M]+ 278.1307; found
278.1320.
or as KBr discs. Wavenumbers (ν) are given in cm–1. Mass spectra
˜
were obtained at 70 eV with a GC-TOF micromass spectrometer
(Micromass Manchester Waters Inc.) for EI. ESI mass spectra were
obtained with a Q-TOF micromass spectrometer (Micromass Man-
chester Waters Inc.).
2-(4-Methoxyphenyl)-5-phenylfuran (15bb): This compound was ob-
tained by the General Procedure, from 12b (228 mg, 1.3 mmol),
the diazonium salt 13b (250 mg, 1.3 mmol) and chloranil (398 mg,
1.6 mmol, 1.2 equiv.). The crude product was purified by column
chromatography on silica gel with a mixture of hexane/MTBE
(50:1) as eluent. Yield of 15bb: 172 mg (0.7 mmol, 53%), m.p. 115–
118 °C. 1H NMR (300 MHz, CDCl3): δ = 7.73 (dd, J = 8.5, 1.3 Hz,
2 H, 3-H), 7.68 (d, J = 8.9 Hz, 2 H, 10-H), 7.41 (dd, J = 7.4, 6.5 Hz,
2 H, 2-H), 7.25 (dd, J = 8.5, 7.4 Hz, 1 H, 1-H), 6.95 (d, J = 8.9 Hz,
2 H, 11-H), 6.72 (d, J = 3.5 Hz, 1 H, 6-H/7-H), 6.61 (d, J = 3.5 Hz,
1 H, 7-H/6-H), 3.85 (s, 3 H, 13-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.1, 153.5, 152.7, 130.9, 128.7, 127.1, 125.2, 123.9,
General Procedure for One-Flask RCM/Oxidation: Catalyst A
(41 mg, 5 mol-%) was added to a solution of the appropriate diallyl
ether 11 (1.0 mmol) in dry and degassed toluene (20 mL). The solu-
tion was stirred at 50 °C for 90 min, and the appropriate oxidant
was then added. The mixture was heated to 90 °C for 20 h, allowed
to cool to ambient temperature and diluted with water. The organic
layer was separated, and the aqueous layer was extracted with
MTBE. The combined organic extracts were dried with MgSO4
and filtered, and the solvents were evaporated. The residue was
purified by column chromatography on silica.
123.6, 114.2, 107.2, 105.7, 55.3 ppm. IR (KBr disc): ν = 1602, 1499,
˜
2-Phenethylfuran (17a): This compound was obtained by the Gene-
ral Procedure, from the diallyl ether 11a (304 mg, 1.5 mmol) and
DDQ (685 mg, 3.0 mmol, 2.0 equiv.). Yield of 17a: 132 mg
1485, 1440, 1297, 1250, 1178, 1114, 1028, 928, 833, 787, 760,
692 cm–1. LRMS (EI): m/z (%) = 77 (15), 125 (14), 178 (21), 207
(15), 235 (70), 236 (13), 250 (100) [M]+. HRMS (EI): calcd. for
C17H14O2 [M]+ 250.0994; found 250.0985. C17H14O2 (250.29): C
81.6, H 5.6; found C 81.3, H 5.4.
1
(0.8 mmol, 51%). H NMR (300 MHz, CDCl3): δ = 7.34 (dd, J =
1.8, 0.8 Hz, 1 H, 1-H), 7.32–7.17 (5 H, Ph), 6.29 (dd, J = 3.1,
1.9 Hz, 1 H, 2-H), 5.98 (dd, J = 3.1, 0.7 Hz, 1 H, 3-H), 2.93–3.01
(4 H, 5-H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.4,
141.2, 140.9, 128.4, 128.3, 126.0, 110.1, 105.1, 34.4, 29.9 ppm.
2-(4-Methoxy-3-nitrophenyl)-5-(4-methoxyphenyl)furan (15bc): This
compound was obtained by the General Procedure, from 12b
(240 mg, 1.4 mmol), the diazonium salt 13c (366 mg, 1.4 mmol)
and chloranil (419 mg, 1.6 mmol, 1.2 equiv.). The crude product
was purified by column chromatography on silica gel with a mix-
ture of hexane/MTBE (3:1) as eluent. Yield of 15bc: 316 mg
2-(4-Methoxyphenyl)furan (17b): This compound was obtained by
the General Procedure, from the diallyl ether 11b (202 mg,
1.0 mmol) and chloranil (293 mg, 1.2 mmol, 1.2 equiv.). Yield of
17b: 83 mg (0.5 mmol, 48%). 1H NMR (300 MHz, CDCl3): δ =
7.62 (d, J = 9.0 Hz, 2 H, 6-H), 7.44 (dd, J = 1.8, 0.8 Hz, 1 H, 1-
H), 6.94 (d, J = 9.0 Hz, 2 H, 7-H), 6.52 (dd, J = 3.3, 0.8 Hz, 1 H,
3-H), 6.46 (dd, J = 3.3, 1.8 Hz, 1 H, 2-H), 3.82 (s, 3 H, 9-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.0, 154.0, 141.4, 125.3, 124.1,
114.1, 111.5, 103.4, 55.4 ppm.
1
(1.0 mmol, 71%), m.p. 128–130 °C. H NMR (300 MHz, CDCl3):
δ = 8.17 (d, J = 2.2 Hz, 1 H, 4Ј-H), 7.85 (dd, J = 8.8, 2.2 Hz, 1 H,
4-H), 7.66 (d, J = 9.0 Hz, 2 H, 11-H), 7.12 (d, J = 8.8 Hz, 1 H, 3-
H), 6.95 (d, J = 9.0 Hz, 2 H, 12-H), 6.69 (d, J = 3.5 Hz, 1 H, 7-H/
8-H), 6.60 (d, J = 3.5 Hz, 1 H, 8-H/7-H), 4.00 (s, 3 H, 14-H), 3.85
(s, 3 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.3, 154.1,
151.2, 150.1, 139.9, 128.8, 125.2, 124.1, 123.4, 120.6, 114.3, 111.9,
General Procedure for the One-Flask Heck Arylation/Oxidation Se-
quence: NaOAc (3.0 equiv.), Pd(OAc)2 (5 mol-%) and the appropri-
ate diazonium salt 13 (1.0 equiv.) were added to a solution of the
appropriate dihydrofuran 12 (1.0 equiv.) in acetonitrile (10 mL per
mmol of 12). The reaction mixture was stirred at ambient tempera-
ture until the evolution of nitrogen had ceased (approx. 15 min),
and the appropriate oxidant was added. The reaction mixture was
107.7, 105.7, 56.7, 55.4 ppm. IR (KBr disc): ν = 1624, 1596, 1524,
˜
1499, 1352, 1280, 1251, 1177, 1024, 868, 833, 784, 688 cm–1. LRMS
(EI): m/z (%) = 59 (15), 310 (17), 325 (100) [M]+, 326 (18) [M + H]+.
HRMS (EI): calcd. for C18H15O5N [M]+ 325.0950; found 325.0935.
2-Phenyl-5-(3,4,5-trimethoxyphenyl)furan (15cd): This compound
was obtained by the General Procedure, from 12c (188 mg,
4820
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Ru- and Pd-Catalysed One-Flask Synthesis of 2-Arylfurans
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1.2 mmol), the diazonium salt 13d (363 mg, 1.3 mmol) and
chloranil (393 mg, 1.5 mmol, 1.2 equiv.). The crude product was
purified by column chromatography on silica gel with a mixture of
hexane/MTBE (7:1) as eluent. Yield of 15cd: 313 mg (1.0 mmol,
[8]
1
78%), m.p. 85–88 °C. H NMR (300 MHz, CDCl3): δ = 7.73 (dd,
[9]
J = 8.6, 1.3 Hz, 2 H, 11-H), 7.42 (dd, J = 7.4, 6.5 Hz, 2 H, 12-H),
7.28 (ddm, J = 7.1, 5.6 Hz, 1 H, 13-H), 6.96 (s, 2 H, 4-H), 6.74 (d,
J = 3.5 Hz, 1 H, 7-H/8-H), 6.67 (d, J = 3.5 Hz, 1 H, 8-H/7-H), 3.95
(s, 6 H, 14-H), 3.89 (s, 3 H, 1-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.6, 153.2, 153.2, 138.0, 130.7, 128.7, 127.3, 126.5,
[10]
[11]
[12]
123.7, 107.3, 106.9, 101.3, 60.9, 56.2 ppm. IR (KBr disc): ν = 1591,
˜
1497, 1463, 1417, 1342, 1248, 1173, 1127, 1025, 1005, 966, 923,
834, 787, 759, 691 cm–1. LRMS (EI): m/z (%) = 105 (10), 140 (9),
155 (10), 181 (17), 295 (70), 296 (13), 310 (100) [M]+. HRMS (EI):
calcd. for C19H18O4 [M]+ 310.1205; found 310.1217.
[13]
[14]
[15]
Methyl 5-[5-(Benzyloxymethyl)furan-2-yl]-2-methoxybenzoate (15de):
This compound was obtained by the General Procedure, from 12d
(148 mg, 0.8 mmol), the diazonium salt 13e (219 mg, 0.8 mmol)
and DDQ (213 mg, 0.9 mmol, 1.2 equiv.). The crude product was
purified by column chromatography on silica gel with a mixture of
hexane/MTBE (5:1) as eluent. Yield of 15de: 177 mg (0.7 mmol,
65%; 84% based on recovered 14de). 1H NMR (300 MHz, CDCl3):
δ = 8.10 (d, J = 2.3 Hz, 1 H, 4Ј-H), 7.78 (dd, J = 8.7, 2.3 Hz, 1 H,
4-H), 7.40–7.27 (5 H, aryl), 7.00 (d, J = 8.8 Hz, 1 H, 3-H), 6.54 (d,
J = 3.3 Hz, 1 H, 7-H/8-H), 6.40 (d, J = 3.3 Hz, 1 H, 8-H/7-H), 4.59
(s, 2 H, 11-H), 4.54 (s, 2 H, 10-H), 3.94 [s (br), 3 H, 17-H/1-H],
3.93 (br. s, 3 H, 1-H/17-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.4, 158.4, 153.2, 151.2, 137.9, 128.8, 128.4, 127.9, 127.7, 127.3,
123.5, 120.4, 112.4, 111.6, 104.9, 71.9, 63.9, 56.2, 52.1 ppm. IR
[16]
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[21]
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[23]
(neat): ν = 129, 1488, 1454, 1535, 1312, 1273, 1229, 1182, 186,
˜
1069, 1021, 820, 785, 737, 697, 603 cm–1. LRMS (EI): m/z (%) =
59 (15), 77 (14), 91 (46), 115 (13), 172 (13), 245 (100), 246 (28), 352
(33) [M]+. HRMS (EI): calcd. for C21H20O5 [M]+ 352.1311; found
352.1307. C21H20O5 (352.38): C 71.6, H 5.7; found C 71.6, H 5.7.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for attempted dehydrogenation reactions
with Shvo’s catalyst including characterization data for the ring-
cleavage products 18 and 19, full analytical data for all furans 15
and 17, numbering schemes for signal assignment and copies of 1H
and 13C NMR spectra for all compounds.
Acknowledgments
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG) (grant 1095/6-1). We thank Evonik Oxeno for
generous donations of solvents, and Umicore, Hanau (Germany)
for a generous donation of Pd(OAc)2.
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Eur. J. Org. Chem. 2011, 4814–4822