Gold catalysis: Catalyst oxidation state dependent dichotomy in the cyclization of furan-yne systems with aromatic tethers

Article abstract of DOI:10.1002/chem.201202004

Four different synthetic strategies led to a variety of furan-yne systems that contained an aryl system in the tether. Due to the short routes to these systems (four steps or less), a small library of substrates could easily be prepared. These were treate

Full text of DOI:10.1002/chem.201202004

DOI: 10.1002/chem.201202004
Gold Catalysis: Catalyst Oxidation State Dependent Dichotomy in the
Cyclization of Furan–Yne Systems with Aromatic Tethers
A. Stephen K. Hashmi,*[a, b] Julia Hofmann,[a] Shuai Shi,[a] Alexander Schꢀtz,[a]
Matthias Rudolph,[a] Christian Lothschꢀtz,[a] Marcel Wieteck,[a] Miriam Bꢀhrle,[a]
Michael Wçlfle,[b] and Frank Rominger[a, c]
Abstract: Four different synthetic strat-
egies led to a variety of furan–yne sys-
tems that contained an aryl system in
the tether. Due to the short routes to
these systems (four steps or less), a
small library of substrates could easily
be prepared. These were treated with
AuCl3 or with the Gagoszꢀs catalyst
Ph3PAuNTf2 complex. The AuCl3-cata-
lyzed reactions delivered highly substi-
tuted fluorene derivatives, a class of
compounds of great importance as pre-
cursors for luminophores with extraor-
dinary abilities. Conversely, a different
mechanistic pathway was observed
with the cationic gold(I) catalyst. In
the latter case, a mechanistically inter-
esting reaction cascade initiated
a
formal alkyne insertion into the furyl-
sp3-C bond, which gave indene deriva-
tives as the final products. This new re-
action pathway depends on the aromat-
ic moiety in the tether, which stabilizes
a crucial cationic intermediate as a
benzylic cation.
Keywords: acids · alkynes · gold ·
insertion · oxygen heterocycles
Introduction
has inspired organic chemists working in total synthesis and
thus the application of gold in natural-product synthesis is
also an emerging field.[5] Our group reported the synthesis
of various benzo-annelated heterocycles by reaction of dif-
ferent furan–yne systems that have a terminal alkyne moiety
(Scheme 1,left).[6] Furthermore, by using alkynyl ethers and
In the field of transition-metal-catalyzed transformations,
gold catalysis has emerged from being a rarity at the end of
the last millennium to one of the most frequently investigat-
ed and applied synthetic tools. This has been summarized in
numerous reports on highly di-
verse reactions.[1]
Most of these reactions can
be performed under very mild
conditions without precau-
tions[2] and in a highly atom-
economic[3] fashion. Of these
Scheme 1. Based on the phenol synthesis (left), fluorene formation should be easy (right).
reports, substrates with an en–
yne substructure offer a huge
number of possible rearrange-
ments that lead to highly complex target molecules. The
ynamides, even nonterminal alkynes could be converted and
new mechanistic pathways were opened with these sub-
strates.[7]
high increase in molecular complexity[4] in these reactions
Herein we focus on the exploration of terminal furan–yne
systems that have aromatic tethers, which could be useful
precursors for the synthesis of substituted fluorenes (Sche-
me 1,right).
[a] Prof. Dr. A. S. K. Hashmi, J. Hofmann, S. Shi, A. Schꢁtz,
Dr. M. Rudolph, Dipl.-Chem. C. Lothschꢁtz, M. Wieteck,
Dr. M. Bꢁhrle, Dr. F. Rominger
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢂt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-54-4205
Fluorenes represent an extremely important class of sub-
strates because fluorene-based polymers and oligomers and
their application in organic light-emitting diodes and organic
photovoltaic cells is of considerable interest.[8] Most of the
synthetic strategies for substituted fluorenes are based on
functionalization of the existing fluorene core. The advant-
age of furans as a starting material is based on the ease of
chemical modification of the furan core[9] and on the oppor-
tunity to synthesize unsymmetric fluorene substructures.
Furthermore, depending on the retrosynthetic disconnection
E-mail: hashmi@hashmi.de
[b] Prof. Dr. A. S. K. Hashmi, Dr. M. Wçlfle
Institut fꢁr Organische Chemie
Universitꢂt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
[c] Dr. F. Rominger
Crystallographic investigation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202004.
382
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Chem. Eur. J. 2013, 19, 382 – 389

FULL PAPER
Table 1. Synthesis of protected furylbenzyl alcohols 4.
of the furan–yne precursors, an easy modification at
the decisive 9-position of the fluorene moiety
would become feasible.[10] However, it must be
noted that similar substrates with a substituted
alkyne give naphtols,[11] thus the observation of flu-
orenes would represent a new reaction pathway for
that type of furan–yne.
Entry Aldehyde 1
Nucleophile Time Yield Yield Product 4
Yield
[%]
[h]
of 2
of 3
[%]
[%]
Results and Discussion
Our synthesis of the substrates started from com-
mercially available 2-bromobenzaldehydes, which
were easily converted to the corresponding alkynyl-
benzaldehydes 1 by Sonogashira reactions with
TMS-acetylene (TMS = trimethylsilyl). The reac-
tions gave high yields at room temperature when
using the common and simple (PPh3)2PdCl2/CuI cat-
alyst system. The next step is a nucleophilic addi-
tion of a metalated arene moiety, which gave alky-
nylbenzylic alcohols 2 in high yields. By using this
strategy, we could not only incorporate furan and
substituted furan moieties (Table 1, entries 1, 2, 5,
6, 7, 9, 10) but also thiophene substituents (Table 1,
entries 3, 8, 11) and a phenyl moiety (Table 1,
entry 4). The latter substrates represent valuable
precursors for the installation of two aromatic moi-
eties at the benzylic position, and their further con-
version will be discussed later. All the furan sub-
strates were then deprotected by using TBAF
(TBAF = tetrabutylammonium fluoride) in THF.
The protecting group could easily be cleaved within
a short reaction time, and yields were excellent in
most cases. To avoid a competing attack of the alco-
hol nucleophile in the gold-catalyzed step, the ben-
zylic oxygen was subsequently protected with
TBSCl (TBSCl = tert-butyldimethylsilyl chloride), a
protecting group that is known to be stable under
gold-catalysis conditions.[12] Unfortunately, the
yields proved to be only moderate for this reaction
step. One reason might be a competing Reppe-type
vinylation,[13] which would lead to methylene dihy-
droisobenzofuran compounds. These are sensitive
and polymerize easily. Thanks to the comment of
one referee, we also tested TBSOTf at 08C for one
substrate and yields could indeed be significantly
improved by using this procedure (Table 1, entry 2,
compound 4b). Nevertheless, all fluorene precur-
sors 4 were available in an efficient three-step pro-
cedure from alkynyl benzaldehydes 1.
3a,
1
1
2a, 98
47
>99[a]
3b,
>99
45/
2
1a
3
2b, 86
2c, 93
69[b]
3
4
1a
1a
3
2
–
–
–
–
–
–
2d,
72[c]
5
6
3
5
2e, 50 3e, 89
2 f, 52 3 f, 90
2g, 88 3g, 96
48
34
1b
7
8
9
6
61
–
1c
3
2h, 63
–
–
3 d
2i, 84 3i, 58
47
10
11
1d
1d
3 d
2j, 64 3j, 88
70
–
1
2k, 88
–
–
[a] KF was used as a deprotecting reagent. [b] Obtained by using TBSOTf at 08C.
[c] Phenylmagnesium bromide was used as a nucleophile.
Due to the easy availability of furfurals from re-
newable feedstocks,[14] a different disconnection of furylben-
zyl alcohols 2 was also explored. For this approach, ortho-al-
kynyl bromobenzene 5 was lithiated by using a metal halo-
gen exchange. The resulting nucleophile reacted successfully
with the furfural part in good yield. In analogy to the other
arylbenzyl alcohols 2a–j, alcohols 2l and 2m were trans-
formed to the desired substrates 4l/4m through a simple de-
protection/reprotection strategy in good overall yields
(Scheme 2).
In addition to protected benzylic alcohols, substrates with
two aromatic substituents at the benzylic position were also
investigated. The direct preparation of substrates with sym-
Chem. Eur. J. 2013, 19, 382 – 389
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383

A. S. K. Hashmi et al.
Scheme 2. Synthetic approach using furfural derivatives as starting materials.
metrically substituted benzylic positions was possible from
aryl benzaldehyde 1a, in analogy to a procedure of Butin
et al.[15] This addition of aromatic nucleophiles to aldehydes,
catalyzed by using perchloric acid, gave desired product 6a
in moderate yield (Scheme 3). After deprotection with
steps vs. 58% for the one-step synthesis of 6a). In these
cases we started from aryl/heteroaryl benzylalcohols 2. In a
subsequent reaction step, an addition of 2-methyl furan, cat-
alyzed by using perchloric acid, gave protected triarylme-
thane derivatives 6 (Table 2). By using this two-step proce-
dure, two different aryl moieties could easily be installed at
the benzylic position, which provided the opportunity to
create a small library of substrates. Yields for the addition
step were all high and, as in the above cases, TBAF depro-
tection smoothly delivered the desired compounds in excel-
lent efficiency.
With these substrates in hand, we explored their reactivity
by using simple goldACTHNUTRGNEUNG(III) chloride as a pre-catalyst. Table 3
summarizes the results obtained with protected furyl alco-
hols 4. To our delight, substrate 4a displayed significant re-
activity and substituted fluorenol 8a was obtained in reason-
able yields (Table 3, entry 1). The high reactivity of this
system (the reaction was complete within minutes at room
temperature!) probably resulted from the fixed geometry of
the incorporated aryl bond, which led to a lower degree of
conformational freedom compared with the substrates with
aliphatic side chains (see also Figure 1). Next, we investigat-
ed monosubstituted furan–yne system 4b (Table 3, entry 2).
Aliphatic side chains were used to deliver regioisomeric
phenol systems in these cases,[6a] but only one product was
formed in the case of the aryl-containing tether. The struc-
ture, which contained the hydroxy moiety in the 4-position
of the fluorene system, was unambiguously proven by an X-
ray crystal structure analysis (Figure 2, left).[16] The reason
for the high selectivity can be explained by a selective ring
opening of the intermediate arene oxides;[17] a regioselective
ring opening exclusively delivers a carbocation that is com-
plimentarily stabilized by the aromatic ring in the tether
(Scheme 4).[18] A comparable effect was previously observed
in the conversions of furan–yne systems that contained ter-
minal ynamides and alkynylethers, which were also able to
stabilize the cationic intermediates through the heteroatom
effect.[6f] Next, we investigated the functional-group toler-
ance towards different substitutents at the aromatic moiety
in the tether. Higher yields were obtained with the electron-
rich protected catechol derivative 4e than with the benzene
derivatives (Table 3, entry 3). Most unfortunately, this effect
was not observed with monosubstituted furan 4 f and the
yield was in the range of the benzene substrate (Table 3,
entry 4). By switching to even more electron-donating me-
Scheme 3. Acid-catalyzed difurylation of benzaldehyde 1a.
TBAF, starting material 7a was accessible. Both compounds
gave crystals suitable for X-ray crystal structure analysis
(Figure 1).[16] The two structures nicely document the loss of
conformational freedom caused by the (Z)-like double bond
of the aromatic system in the tether, which brings the react-
ing centers close together.
Figure 1. ORTEP plots of 6a (left) and 7a (right). Thermal ellipsoids are
drawn at the 50% level of probability.
Unfortunately, substituted benzaldehydes 1b and 1c de-
composed. Thus, we considered a two-step procedure that
turned out to be much more successful (e.g., 85% over two
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Cyclization of Furan–Yne Systems with Aromatic Tethers
FULL PAPER
Table 2. Two-step synthesis of triarylmethane derivatives 7.
Table 3. GoldACTHNGUTERNNU(G III)-catalyzed conversion of furan–yne systems 4.
Entry Starting material Time [min] Product 8
Yield of 8 [%]
Entry 2
Yield of 6
Product 7
Yield of 7
[%]
[%]
1
2
4a
4b
10
5
60
1
6a, 87
6b, 84
6c, 83
6d, 94
97
99
97
98
51
74
2
3
4
3
4
4e
4 f
5
5
50
5
6
4g
4i
5
decomposition
–
10
38
7
8
9
4j
10
50
–
4l
5
decomposition
5
6
7
6e, 69
6 f, 93
6g, 68
92
97
81
4m
10 min
24
thoxy groups in catechol derivative 4g, an unselective reac-
tion was observed and a complex mixture was obtained
even in the case of the substituted furan system (Table 3,
entry 5). In full agreement with these observations, substrate
4i with electron-deficient m-fluorobenzene in the tether led
to an explicit decrease in yield (Table 3, entry 6). Interest-
ingly, switching the chain length of the substituent on the
furan system from a methyl to a pentyl group re-established
an acceptable yield for these systems (Table 3, entry 7). To
further explore the influence of the furan substituent, sub-
strate 4l, which has an aryl group, was converted. However,
only decomposition was observed, even at 08C, after short
reaction times. This is in contradiction to the previous stud-
ies,[6e] but here the protected hydroxyl moiety in the strongly
Figure 2. Solid-state molecular structures of 8b (left) and 8m (right).
Thermal ellipsoids are drawn at the 50% level of probability.
activated furyl position might open degradation pathways
via cationic intermediates. In the case of tri-substituted
Chem. Eur. J. 2013, 19, 382 – 389
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385

A. S. K. Hashmi et al.
Table 4. GoldACTHNUGRTNEUNG(III)-catalyzed conversion of furan–yne systems 7.
Scheme 4. Regioselective ring-opening pathway via benzyl stabilized cat-
ACHTUNGTRENNUNGions.
Entry Starting material Time T [8C] Product 9
Yield of 9 [%]
1
2
7a
7b
10 min
0
79
furan system 4m, only a low yield of the expected product
was isolated and, as in previous reports on this substitution
pattern, byproducts were detectable by TLC but were not
stable upon isolation.[18] Nevertheless, crystals suitable for
X-ray analysis were obtained that prove the positioning of
the methyl groups in the 2- and 3-positions of the newly
formed fluorene core (Figure 2, right).[16]
40 min À30
69
51
Encouraged by these findings, we also explored the reac-
tivity of triarylmethane derivatives 7. As in the previous
case, they were converted by simple AuCl3 in CH2Cl2. The
results are summarized in Table 4. Similarly to the corre-
sponding furylalcohol derivative 4a, a fast conversion was
observed for substrate 7a even at 08C (Table 4, entry 1).
Furthermore, the yield was significantly higher in this case.
Because some experiments for the conversion of diaryl sub-
strates showed a tendency for polymerization as well as cat-
alyst deactivation even at 08C, the other 7b–g systems were
all converted at much lower temperatures (À608C). Even
under these remarkably mild reaction conditions, difuryl-
substituted 7b and 7c were converted regardless of whether
electron-deficient (7b, Table 4, entry 2) or electron-donating
substituents (7c, Table 4, entry 3) were attached to the aro-
matic core. The discrepancy in yield is not based on the in-
trinsic reactivity of these systems, but on the instability of
some of the compounds during isolation processes (all of
the reactions showed complete and selective conversion that
could be monitored by TLC). Switching to thiophene-con-
taining substrates 7d–f (Table 4, entries 4–6) revealed the
same picture. In all of these substrates, only the furan
moiety served as a nucleophile and no competing pathways
via an attack of the thiophene moiety were observed. Yields
for these substrates were comparable with the furan systems
and in addition to test substrate 7d with a nonsubstituted ar-
omatic system (Table 4, entry 4), both electron-deficient
(Table 4, entry 5) and electron-donating groups (Table 4,
entry 6) delivered acceptable yields even under these re-
markably mild reaction conditions. Finally, we explored the
reactivity of phenyl-substituted precursor 7g. In this case se-
lective fluorene formation also took place, but slightly
slower reaction rates were monitored (Table 4, entry 7).
Because gold(I) sources are increasingly dominating the
field of homogeneous gold catalysis, we tested several of our
substrates with the air-stable and storable Gagosz catalyst
Ph3PAuNTf2.[19] Table 5 summarizes the results. To our sur-
prise, the conversion of starting material 4b under gold(I)
conditions did not deliver the expected fluorene substrate
8b, although a selective transformation to an unpolar com-
pound was observed. Most unfortunately, this compound
3
7c
2 h
3 h
À60
À40
4
5
7d
7e
68
65
45 min À30
6
7
7 f
7g
2 h
6 h
À40
À60
55
57
was not stable for a prolonged time and attempts to isolate
it by using column chromatography failed (with both silica
and even basic alumina oxide). Finally, we succeeded in sta-
bilizing this compound by simple filtration of the catalyst
over a pad of Celite, and obtained a stable compound in
pure form. NMR spectroscopy data of this compound indi-
cate that the substructure of the monosubstituted furan
moiety is still present in the product (characteristic J values
of 3.4 and 1.7 Hz for the furan couplings). Furthermore, the
alkyne moiety is transformed into a trisubstituted double
bond and the protected benzyl alcohol moiety is also still
present (assigned by a doublet at d=5.39 ppm in the
1H NMR spectrum and the corresponding tertiary carbon at
d=78.8 ppm in the 13C NMR spectrum). In combination
with additional 2DNMR experiments, the substructure of a
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Cyclization of Furan–Yne Systems with Aromatic Tethers
Table 5. Gold(I)-catalyzed synthesis of indenes.
FULL PAPER
Entry
1
Starting material
Product 10
Yield of 10 [%]
4b
70
2
3
4
4 f
4g
4j
>99
–
complex mixture
>99
5
6
4l
80
–
4m
complex mixture
3-furyl-substituted indene with a protected hydroxy function
in the 1-position could be assigned (Table 4, entry 1, 10b).
To explore the generality of this reaction pathway, different
benzyl furyl alcohols were converted by using the gold(I)
catalyst. Owing to the styrene analogue system in the prod-
ucts, only filtration from the catalyst over celite was possible
as a purification step, but no side products were visible
except for substrates 4g and 4m (Table 4, entries 3, 6),
which delivered complex mixtures most probably based on
polymerization of the resulting electron-rich styrene-like
products. All of the starting materials were completely con-
sumed after 1 h, regardless of whether electronically neutral
(Table 4, entries 1, 5, 6), electron-rich (Table 4, entries 2, 3),
or electron-deficient (Table 4, entry 4) arenes were incorpo-
rated in the tether. Interestingly, even substrate 4l, which re-
acted unselectively during fluorene formation, selectively
delivered the indene product in high yields (Table 4,
entry 5). Possibly this substrate partly reacts via the indene
Scheme 5. Proposed mechanism, with the chemoselectivity-determining
step after intermediate I.
carbon–oxygen bond) and gold carbenoid II is formed
(Pathway 1). Nucleophilic attack of the carbonyl oxygen
onto the carbenoid carbon followed by rearrangement of
the resulting oxepine/arenoxide tautomers finally delivers
fluorene derivatives I/H by the known phenol pathway.
From cationic intermediate I, Pathway 2 is initiated by
cleavage of a carbon–carbon bond. This mechanistic path-
way becomes attractive due to the stabilization of the result-
ing benzylic cation by the electron-donating group in sub-
strates 4. In addition, rearomatization of the furan system is
achieved. Intermediate III then can be cyclized through
attack of the double bond of the vinyl–gold moiety. In the
last step of the cascade, cyclic intermediate IV liberates the
catalyst through formation of the styrene-like double bond
in products J. Considering this mechanistic puzzle, the trig-
ger for a particular pathway might be the ability for back
donation of the gold catalyst in intermediate I. If one starts
with the neutral AuCl3 catalyst (compared with the positive-
ly charged AuI salt), a stronger back donation of the formal-
ly À1 charged Au catalyst becomes obvious.
pathway even with gold
product is not stable under the stronger Lewis-acidic condi-
tions of the gold(III) catalyst. Further studies concerning
ACHTUNGTRNE(NUNG III) catalysts, and the resulting
ACHTUNGTRENNUNG
these two possible reaction pathways involving diarylme-
thane derivatives 7 are underway and will be published else-
where.
A
possible mechanistic rationale is summarized in
Scheme 5. The initial step of the reaction cascade for both
pathways consists of a 5-exo-dig cyclization of the enyne
system, which delivers stabilized cationic intermediate I.[20]
From here two mechanistic pathways are conceivable. Based
on the donation of charge from the gold catalyst, a subse-
quent ring opening of the furan takes place (cleavage of the
To verify this assumption, we performed the conversion of
substrate 4b and analyzed the selectivity depending on the
nature of the catalyst (Table 6). In fact, a clean formation of
Chem. Eur. J. 2013, 19, 382 – 389
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387

A. S. K. Hashmi et al.
Table 6. Reactions of 4b with different gold(I) and goldACTHNUTRGNEUNG
(III) catalysts.[a]
stitution. Because these systems could be useful precursors
for optically active materials, the variability of the starting
materials and their easy accessibility makes this route ex-
tremely attractive. As well as possible variations at the furan
core, substitutions at the important 9-position of the result-
ing fluorene core can be easily achieved through simple and
convergent synthetic approaches to the starting materials.
Herein we investigated two different subclasses of fluorene
derivatives and further variations are under investigation in
our group.
Entry
Catalyst [3 mol%]
Solvent
Selectivity
1
2
IPrAuNTf2
IPrAuCl3
CD2Cl2
CD2Cl2
only 10b
only 8b
3
4
5
CD2Cl2
CD2Cl2
CD2Cl2
only 8b
only 8b
only 8b
Based on the ability to stabilize cationic intermediates
through the benzylic positions of the incorporated aromatic
system in the tether, a new reaction pathway was opened by
using cationic gold(I) complexes for the conversions. Here, a
new cleavage of the carbon–carbon bond instead of a cleav-
age of the carbon–oxygen bond (the usual pathway to open
the furan system) took place and an astonishing reaction
cascade finally delivered indene derivatives by a formal in-
À
sertion of the terminal alkyne into a furyl C bond.
6
7
8
9
AuCl
CD2Cl2/CD3CN
CD2Cl2/CD3CN
CD2Cl2/CD3CN
CD2Cl2/CD3CN
only 8b
AuCl+AgNTf2 (1:1)
AuCl3 +AgOTf (1:1)
AuCl3 +AgOTf (1:3)
decomposition
decomposition
decomposition
Acknowledgements
[a] All reactions were monitored by using NMR spectroscopy with hexa-
ACHTUNGTRENNUNGmethylbenzene as the internal standard.
The authors thank Umicore AG & Co. KG for the generous donation of
gold salts.
product 10b was also detected when using a charged cation-
ic gold(I) complex with a carbene ligand (Table 6, entry 1).
For the corresponding goldACTHNURGTNE(NUG III) carbene complex, no activa-
tion by a silver salt was necessary (Table 6, entry 2). If one
considers the square-planar nature of the precatalyst, it be-
comes obvious that a halogen should dissociate before sub-
strate activation can take place. Therefore, the active cata-
lyst should be a cationic species as well, but nevertheless flu-
orene 8b was formed exclusively. Pyridine carboxylate as
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the ligand on the goldACTHNUGRTENUNG(III) center showed the same result
(Table 6, entry 3), even if additional silver additives were
added as halide scavengers (Table 6, entries 4, 5). In con-
trast, gold(I) chloride in the absence of a silver source
turned out to be the exception (Table 6, entry 6). Even with
the gold(I) oxidation state, only compound 8b was formed.
This indicates that charge might also play a role for the re-
action selectivity, but one could also consider a disproportio-
nation of the less-stabilized gold(I) precursor into gold
and gold(0). Attempts to generate cationic complexes by
mixing gold(I) or gold(III) chloride with silver additives de-
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388
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Chem. Eur. J. 2013, 19, 382 – 389

Cyclization of Furan–Yne Systems with Aromatic Tethers
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Received: June 6, 2012
Revised: September 26, 2012
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Published online: November 13, 2012
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