Synthesis of Fulvene Vinyl Ethers by Gold Catalysis

Article abstract of DOI:10.1002/chem.202000338

Gold-catalyzed cyclization of 1,5-diynes with ketones as reagents and solvent provides diversely substituted vinyl ethers under mild conditions. The regioselectivity of such gold-catalyzed cyclizations is usually controlled by the scaffold of the diyne. H

Full text of DOI:10.1002/chem.202000338

A Journal of
Accepted Article
Title: Synthesis of Fulvene Vinyl Ethers by Gold Catalysis
Authors: Alexander Ahrens, Julia Schwarz, Danilo M. Lustosa, Rahele
Porkaveh, Marvin Hoffmann, Frank Rominger, Matthias
Rudolph, Andreas Dreuw, and A. Stephen K. Hashmi
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To be cited as: Chem. Eur. J. 10.1002/chem.202000338
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10.1002/chem.202000338
Chemistry - A European Journal
RESEARCH ARTICLE
Synthesis of Fulvene Vinyl Ethers by Gold Catalysis
Alexander Ahrens,[a] Julia Schwarz,[a] Danilo M. Lustosa,[a],[b],[#] Raheleh Pourkaveh,[a],[c] Marvin
Hoffmann,[b],[#] Frank Rominger,[a],[+] Matthias Rudolph,[a] Andreas Dreuw,[b],[#] A. Stephen K. Hashmi[a]*
Abstract: The gold-catalyzed cyclization of 1,5-diynes with ketones
as reagents and solvent provides diversely substituted vinyl ethers
under mild conditions. The regioselectivity of such gold-catalyzed
cyclizations is usually controlled by the scaffold of the diyne. Herein
we report the first solvent-controlled switching of regioselectivity from
a 6-endo-dig- to 5-endo-dig-cyclisation in these transformations,
providing fulvene derivatives. With respect to the functional group
tolerance, aryl fluorides, chlorides, bromides and ethers are tolerated,
Furthermore, the mechanism and selectivity are put to scrutiny by
experimental studies and a thermodynamic analysis of the product.
Additionally, 6-(vinyloxy)fulvenes are a hitherto unknown class of
compounds. Their reactivity is briefly evaluated, to give insights into
their potential applications.
intermediates (Figure 1). In all cases the regioselectivity of the
cyclisation is controlled by the substitution pattern of the 1,5-diyne.
These high energy species can be utilized for the development of
new transformations, yet the reactivity provides a challenge
regarding selectivity.
digold species
[Au]+
monogold species
R
[Au]
[Au]
R
R
R
R
R
[Au]
[Au]
[Au]
aurated
diaurated
aurated
aurated
gold vinylidene
phenyl cation
vinyl cation
phenyl cation
Introduction
Figure 1. Proposed intermediates of gold-catalyzed 1,5 diyne cyclizations.
Starting with the discovery of the gold-mediated dual
activation[1],[2],[3] of 1,5-diynes possessing at least one terminal
alkyne by Zhang et al.[4] and Hashmi et al.[5], our group has
developed a long standing interest in the chemistry of 1,5-
diynes.[3],[6] This seemingly simple scaffold has opened up a rich
chemistry in synergy with gold, triggered by highly reactive
organogold intermediates. The nucleophilic attack of a gold
acetylide onto another alkyne, π-coordinated by gold, leads to
aurated gold vinylidene[4],[5],[7],[8] or diaurated phenyl cation[9],[10],[11]
intermediates, respectively. These highly electrophilic species
enable new synthetic methods.[3] Recently, our group reported the
activation of 1,5-diynes by only one single gold center. In
dependency of the substitution pattern of the substrate, either
aurated vinyl cation[12] or aurated aryl cations[13] are the key
Vinyl ethers are a highly relevant moiety for organic synthesis,
allowing a rich follow-up chemistry.[14] They are used in many
fields, especially the impact on polymer science is noteworthy.[15]
As a scaffold of interest, many protocols for vinyl ether synthesis
have been developed.[16] Hydroalkoxylation of alkynes has been
a central access to vinyl ethers, with Reppe being the pioneer of
that field.[17] Many carbophilic metals catalyse this interesting
transformation, such as mercury,[18] silver[19] and ruthenium[20] to
name but a few, yet often harsh conditions or elaborate starting
materials are necessary. Utimoto and later Teles et al. showed
that gold salts also catalyze the attack of alcohols on alkynes, but
often in favour of giving ketal or ketone products via double
addition.[21] A gold(I)-catalysed approach by Corma et al. gave
convenient conditions for vinyl ethers, but is limited to electron-
poor alkynes.[22] Other gold-mediated methods have been
introduced, giving mild synthetic strategies.[23] The mechanism of
this useful transformation has been thoroughly investigated.[24] In
2013 Shi et al. substituted alcohols for cyclic 1,3-diketones
allowing clean conversion to vinyl ethers via the attack of oxygen.
However, noncyclic 1,3-ketones already failed to give the desired
oxygen addition.[25]
[a]
A. Ahrens., J. Schwarz. Dr. D. M. Lustosa, R. Pourkaveh, F.
Rominger, Dr. M. Rudolph, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Heidelberg University
Im Neuenheimer Feld 270
69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
[b]
[c]
Dr. D. M. Lustosa, M. Hoffmann, Prof. Dr. A. Dreuw
Interdisciplinary Center for Scientific Computing (IWR)
Heidelberg University
Im Neuenheimer Feld 205A
69120 Heidelberg (Germany)
We envisioned a vinyl ether synthesis accessible by simple
starting materials under mild conditions by exploiting the
aforementioned aurated carbocationic intermediates instead of
alkynes as electrophiles and simple ketones instead of alcohols
or 1,3-ketones as nucleophiles. Due to the high reactivity of these
species a kinetic control of the reaction should be feasible
preferring the attack of the carbonyl oxygen instead of the enol
carbon of the respective tautomer, which is only available in very
low concentrations in the reaction mixture. After elimination of a
proton, the vinyl functionality is formed by the former ketone. Such
R. Pourkaveh
Laboratory of Organic Synthesis and Natural Products
Department of Chemistry, Sharif University of Technology
Azadi Street
PO Box 111559516 Tehran (Iran)
Crystallographic investigation
[+]
[#]
Theoretical investigation
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202000338
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RESEARCH ARTICLE
a method would be complementary to the briefly introduced
established methods for vinyl ether preparation.
5 mol% IPr*AuCl/AgNTf2
C6H6, 80 °C
Results and Discussion
1c
2c (58%)
In order to develop this methodology, we started the
investigations with substrate 1b which was, in analogy to our
previous work,[13] supposed to act as a precursor for an aurated
phenyl cation intermediate. However, the previously reported
intramolecular trapping pathways is suppressed by the attached
short side chains. Whether trapping the postulated intermediate
intermolecularly is possible, was tested using benzene as solvent
giving 2b. Next, acetone as a symmetric and common reagent
was tested as solvent. To our delight, by using acetone as solvent
and 2 mol% IPr*Au(MeCN)SbF6 as catalyst a full conversion was
observed yielding the desired product 3b in moderate yield after
4 h at rt (Scheme 1).
2 mol% IPr*Au(MeCN)SbF6
acetone, rt
O
1c
3c (37%)
Scheme 2. Gold-catalyzed cyclisation of 1c in benzene and acetone,
respectively.
Optimization experiments to improve the efficiency of the reaction,
with 1c as substrate, were conducted. As gold salts as π-acids[26]
might also catalyze the hydrolysis of the products in the presence
of water the reagent grade acetone stored under air was
substituted by dry acetone.[27] However, the yield only improved
by a narrow margin up to 41%. Adding 4 Å molecular sieve to the
reaction led to decomposition and an incomplete conversion of
the starting material. An optimized work up with deactivated silica
by using a mixture of PE and NEt3 instead of PE and EA gave a
significant improvement, with 67% of 3c being isolated.
5 mol% IPr*AuCl/AgNTf2
C6H6, 80 °C
2b
3b
1b
1b
(52%)
O
2 mol% IPr*Au(MeCN)SbF6
acetone, rt
Furthermore, we conducted a small catalyst screening (Table 1)
testing bulky carbenes and a phosphine as ligands (Figure 2). A
few counter ions, too, were considered.
(53%)
Table 1. Catalyst and counter ion screening in dry acetone under air, with 2
mol% catalyst loading and a concentration of 150 µmol/ml 1c. All yields are
isolated yields.
Scheme 1. Gold-catalyzed cyclisation of 1b in benzene and acetone,
respectively.
We moved on to the analogous 1,5-diyne with an aromatic
backbone 1c. Methyl groups on the backbone were chosen to
ease investigation by 1H NMR spectroscopy. Remarkably, we
observed that the cyclization mode of this specific substrate can
be altered by the applied solvent/nucleophile. A conducted test
reaction in benzene gave a clean conversion to the respective
naphthalene derivate 2c. In acetone however the selectivity is
switched from a 6-endo-dig to a 5-endo-dig cyclization, as
confirmed by 1H,1H NOESY experiments. This influence of a
solvent on the gold-mediated reactions of 1,5-diynes is
unprecedented to the best of our knowledge (Scheme 2).
Entry
Catalyst
Reaction time
Yield 3c
67%
1
2
3
4
5
6
7
8
9
IPr*Au(MeCN)SbF6
3 h
t
Me4 BuXPhosAu(MeCN)SbF6
4 d
32%
IPrAu(MeCN)SbF6
5 h
39%
[a]
Me2CAACAuCl/ AgSbF6
1 d
24%
[b]
IPr*AuCl/ AgSbF6
3 h
decomposition
no conversion
22%
IPr*AuCl/ NaBArF[b]
IPr*AuCl/ NaBArF[a]
IPr*AuNTf2
2 d[c]
1 d
3 h
34%
AgSbF6
2 d[c]
no conversion
[a] The chloro gold complex and chloride scavenger were dissolved in a 2:1
DCM:MeCN mixture and stirred at rt for 20 min. The solvent was removed in
vacuo and the residue suspended in DCM. This suspension was filtered over a
thin plug of silica, the solvent removed again and 1c dissolved in acetone added
to the residue. [b] The chloro gold complex was dissolved with 1c in acetone,
then the chloride scavenger was added. [c] After one day the reaction was
heated to 60 °C for another day.
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RESEARCH ARTICLE
Ph
Ph
Continuaton of table 2.
Ph
Ph
tBu
tBu
O
N
N
N
N
N
P
iPr
iPr
Au
X
Au
X
Au
X
Au
X
3h (32%)
8
1h
Ph
Ph
Ph
Ph
iPr
O
Me4tBuXPhosAuX
Me2CAACAuX
IPr*AuX
IPrAuX
9
1j
3j (47%)
Figure 2. Complexes used in the catalyst screening.
MeO
10
_______[a],[c]
1k
The initial test system of IPr*Au(MeCN)SbF6 proved to be
superior over all tested conditions. The screening revealed that
albeit silver salts do not consume the starting material, the
presence of silver in the gold catalysis leads to decomposition.
MeO
O
11
1l
3l
(57%)
S
S
With an acceptable yield we moved on to explore if the
transformation can be applied on a broad scope of 1,5-diyne
[a] No reaction at rt with 6 mol% IPr*Au(MeCN)SbF6, heating up to 60 °C led to
decomposition. [b] After 3 h reaction control by TLC showed mixture of product and
starting material, another 2 mol% catalyst were added. [c] Additionally tested with 6 mol%
Me4tBuXPhosAu(MeCN)SbF6 at 60 °C. Again no reaction at rt and decomposition at 60 °C.
systems (Table 2)
.
Table 2. Exploration of scope and limitations. Reactions were carried out with
dry acetone under air and at a concentration of 150 µmol/ml substrat
Eleven substrates were tested, of which only the olefinic
backbone, entry 2, and thiophene backbone, entry 11, gave
vinyloxy arenes. These results are in good agreement with
already established reactivities.[13],[10] The terminal diyne 1a
showed only slow decomposition under the reaction conditions.
Very electron-rich and very electron-poor substrates 1d, 1e and
1k gave no reaction at rt and decomposed slowly upon heating.
Presumably, the products react unselectively at higher
temperatures in the presence of gold salts. Five substrates gave
6-(vinyloxy)fulvenes in moderate to good yields, including a larger
π-system, entry 9, and halogenated compounds, entry 6 and 7.
Crystals suitable for X-ray single crystal structure analysis were
gained by crystallisation of 3j from DCM and pentane at 4 °C,
confirming the compound and its geometry (Figure 3).[28]
entr
starting material
product
_______[a]
O
1a
1b
1c
1d
1
[b]
3b
(53%)
2
3
4
O
3c (67%)
MeO2C
_______[a]
MeO2C
F
F
F
F
5
6
1e
1f
_______[a]
O
Figure 3. Molecular structure of 3j in the crystal. Hydrogen atoms were omitted
for clarity.[28]
Cl
Cl
Cl
Cl
Presuming that aurated vinyl[12] or aryl[13] cations are formed
initially, which then are attacked by the solvent, substituents larger
than methyl on the alkynes of the substrates would be prone to
compete with acetone for the cationic intermediate. To put the
competition of intra- vs intermolecular attack up to scrutiny we
expanded the scope of test substrates (Table 3).
3f
(78%)
(75%)
O
Br
Br
Br
Br
3g
7
1g
Table continued in the next column.
Interesting enough, for the phenyl-substituted 1,5-diyne, entry 1,
the intramolecular attack of the vinyl cation intermediate at the
aromatic ring only occurs to a minor extend, product 4m was
obtained in 6%. Instead, acetone attacks efficiently, giving the 6-
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(vinyloxy)fulvene 3m in 69% yield. Entry 2 shows that a
deactivation of the aromatic system selectively leads to the vinyl
ether 3n, whereas electron-rich arenes give a mixture of both
products (entry 5). The electron-poor system in entry 3 provides
only the dibenzopentalene product 4o. Presumably, the electron-
withdrawing inductive effect of fluorine on the backbone
destabilises the vinyl cation intermediate via the σ-skeleton,
inducing a faster intramolecular attack at the phenyl substituent.
Very electron-rich and very electron-poor backbones (entry 4 and
6), gave no conversion at rt and decomposition at higher
temperatures. The olefinic backbone with alkyl chains only gave
the known[13] intermolecular C,H-insertion product 4s (entry 7).
Figure 4. Solid state molecular structure of 3n. Hydrogen atoms were omitted
for clarity.[28]
Different solvents with carbonyl functionality were also tested
(Table 4). Aldehydes do form the desired product, but the reaction
is far less selective than with ketone nucleophiles. The product
could not be separated from a mixture of unidentified compounds.
Hence, the yield could not be determined. Cyclic ketones reacted
well, except cyclobutanone (entry 2), possibly due to the build-up
of ring strain upon forming a cyclobutenol moiety,[29] inhibiting the
deprotonation of the oxonium intermediate. In case of
unsymmetric ketones, the formation of the vinyloxy group obeys
Hofmann’s rule, giving the kinetic product 3v (entry 6). This
indicates that in the deprotonation step to form the vinyl moiety, a
sterically hindered base is involved, possibly the solvent itself or
the aurated vinyl ether (in the protodeauration). When methanol
was tested as solvent, a double addition of took place, the
observed 5-endo-dig product 5 inditcates that the polarity of the
solvent influences the reaction pathway. Crystals of 5, suitable for
X-ray single crystal structure analysis, were grown from a hot
pentane solution, which was cooled to -32 °C (Figure 5).[28]
Table 3. Intra- and intermolecular reaction of the intermediate. Reactions were
carried out with dry acetone under air and a concentration of 150 µmol/ml
substrate.
Ph
Ph
1
3m (69%)
4m (6%)
1m
CF3
F3C
CF3
O
not
detected
2
3n (66%)
1n
CF3
CF3
CF3
Ph
O
F
F
F
F
Ph
F
Ph
Ph
F
F
F
F
F
F
not
detected
3
4
4o (43%)
1o
1p
Ph
Ph
F
O
O
O
O
[a]
[a]
_
_
Ph
O
MeO
OMe
OMe
O
3q
4q
(20%)
5
(38%)
1q
OMe
O
Ph
O
[a]
[a]
6
_
1r
_
Figure 5. Solid state molecular structure of 5.[28]
O
Ph
O
7[b]
traces[c]
4s (31%)
1s
[a] No reaction at rt with 6 mol% IPr*Au(MeCN)SbF6, heating to 80 °C still gave no conversion. [b] The reaction was stirred for 2
days. [c] Detected by GCMS and characteristic vinyloxy peaks in 1H NMR spectroscopy of the crude reaction mixture.
Here too, the structure was confirmed by X-ray single crystal
structure analysis. Suitable crystals were obtained by
crystallization of 3n from DCM and pentane at 4 °C, confirming
the compound and its geometry (Figure 4).[28]
Table 4. Exploration of scope and limitations. Reactions were carried out with
dry acetone under air and at a concentration of 150 µmol/ml substrate.
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
olefinic backbone:
-cyclisation
aromatic backbone:

-cyclisation
I


RH, rt, 3 to 5h
[Au]+


H
1c
IIa
IIb
O
entry RH
product
[Au]
O
[Au]
detected,
but not
isolated[a]
O
O
1
H
H
O
O
O
[b]
_
2
IIIb
IIIa
1b/ 1h
[Au]
[Au]
- H+
- H+
O
O
3t (52%)
3
O
O
IVb
IVa
[Au]
H+
[Au]
[Au]+
O
H+
O
3u
(45%)
4
5
O
O
O
[c]
_
O
H
H
3h
3b
Scheme 3. Proposed mechanism for the gold-catalyzed formation of 3b and
3h.
O
O
O
not
detected
6
3v
(34%)
Apparently, the more polar environment tends to stabilize the
aurated vinyl cation IIb over the respective aurated aryl cation.
This could mean that the aryl cation is a transition state and not a
true intermediate for this class of compounds.[13] It can be
speculated that a transition state would not benefit as much as a
vinyl cation intermediate from a carbocation stabilizing polar
environment. DFT calculations regarding the influence of solvent
on the intermediates were inconclusive.[31] Either way, these
highly electrophilic species are attacked by the carbonyl oxygen
of the solvent. The resulting aurated oxonium ions IIIa and IIIb
can then eliminate a proton to form the aurated vinyl ethers IV.
Protodeauration in turn releases the respective products 3b and
3h and releases the gold cation back into the catalytic cycles. To
confirm intermediate IVb, the substrate 1c was left to react in
deuterated acetone (Scheme 4). An additional deuteration
experiment using normal acetone and 5% D2O failed, as the
increased water contend let to decomposition.
O
[c]
7
8
_
O
O
O
5
(58%)
OH
[a] Detected via GCMS und 1H NMR spectroscopy, but could not be isolated. No yield
determined [b] No conversion with 6 mol% IPr*Au(MeCN)SbF6 at 50 °C. [c]
Decomposition.
We assume that the mechanism for the different cyclizations
follows principles discussed before (Scheme 3).[12],[13] After π-
coordination of the gold cation to one alkyne unit,[30] the other
alkyne can attack it via its α- or β-carbon to form the two
intermediates IIa and IIb, respectively. The formation of the
benzoid aromatic system is a considerable driving force, resulting
in the formation of the aurated phenyl cation IIa. The aromatic
backbone on the other hand ends up forming a benzofulvene
system. Why the cyclisation mode for substrate 1h is switched
from benzene to acetone could not be answered yet.
Scheme 4. Deuteration experiment. The rate of deuteration was determined
by 1H NMR spectroscopy of the product d6-3c.
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Figure 6. Thermodynamic evaluation of 3h and its isomers (geometries were
optimized using PBE/def2-SV(P) in the gas phase and energies were computed
at the M06/def2-TZVPP level of theory).
To test whether the selectivity of the cyclisation mode can be
“switched” by changing the polarity of the reaction medium, 10 eq.
of acetone were added to 1c dissolved in benzene and left to react
in presence of 2 mol% IPr*Au(MeCN)SbF6. However, even after
several days, only trace amounts of benzene addition product 2c
and no acetone adducts were observed by GCMS. An experiment
using an acetone/benzene mixture 1/3 gave small amounts of 3c
and about 10 to 20% of 2c at low conversion after 16 h, as
confirmed by GCMS and crude 1H NMR spectra. Reliable yields
were not determined from the crude mixture, but no isomers of 3c
or 2c were detected.
This theoretical study shows, that 3h is thermodynamically
unfavored in relation to its potential isomers. That these isomers
could not be detected hints at this transformation being under
kinetic control. This stresses the preparative potential of aurated
vinyl and aryl cations.
To the best of our knowledge, 6 (vinyloxy)fulvenes have not been
synthesized before, yet they have much potential to become a
substructure of interest, combining the chemistry of fulvenes[32]
with the chemistry of vinyl ethers.[14] We evaluated some new
transformations.
First, simple acidic hydrolysis of 3c was tested. As expected, the
vinyl ether functionality was lost. The released enol tautomerized
to give the Michael system 6 in good yield. (Scheme 6)
Acetone acting as an O-nucleophile is unusual. In the beginning
of our studies, we postulated that the high reactivity of the
electrophilic intermediate should be able to enforce a kinetic
control. I.e. that the ketone functioning as nucleophile should
attack the carbocation with its oxygen atom and not via its enol-C.
Both the aurated aryl cation IIa and the aurated vinyl cation IIb
were attacked by the oxygen of the ketone used as solvent, which
seemingly supports our hypothesis. In order to gain further insight
1 mol% p-TSA
or
O
HO
O
2 mol% AgSbF6
into the control of selectivity of this transformation,
a
thermodynamic evaluation of the cyclisation product and its
potential isomers was conducted. For this, the conversion of 1,5-
diyne 1h into enol ether 3h (Scheme 5) was used as basis for
theoretical studies.
THF, rt, air
6 (62 to 75%)
3c
Schema 6. Hydrolysis of vinyl ether 3c.
Since cyclopropanes[33] and fluorine[34] are of high interest in
medicinal chemistry, we wanted to see if our new compound class
could be subjected to the convenient difluorocyclopropanation
established by Prakash et al.[35] To our delight we found that 3m
cleanly converts to the desired geminal difluorocyclopropane 7m
in good yield. For 3c, on the other hand, the more complex
product 7c was isolated in good yield (Scheme 7).
O
O
OH
O
- [Au]+
H
[Au]
IIIb
3h
(32%)
+ [Au]+
O
O
H
[Au]
1h
IIb
F
F
- [Au]+
H
[Au]
IIIb'
O
CF3TMS
10 mol% NaI
O
3h'
Ph
Ph
Ph
Ph
not found
Scheme 5. Found attack of acetone via its carbonyl oxygen atom versus
theoretical C-attack via its enol form.
THF, 65°C
3m
7m
(72%)
Besides the hypothetical isomer 3h’, its tautomers were also
taken into consideration (Figure 6).
F
F
O
CF3TMS
10 mol% NaI
O
THF, 65°C
F
3c
7c
(67%)
Scheme 7. Reaction of 6-(vinyloxy)fulvenes with in situ-generated
difluorcarbene.
Here too, the proposed structure for 7c could be confirmed by X-
ray crystallography (Figure 7).
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Sulfonamide 8 was obtained in good yield after an aqueous work
up and recrystallisation, making for a convenient synthesis of an
interesting compound. In the observed transformation, the vinyl
ether moiety acts as a C-nucleophile, attacking CSI under
substitution of chloride. This reactivity has been observed using
organostannanes as nucleophiles e.g. in Friedel-Crafts type ipso
substitutions.[39] The for olefins more common formation of
β-lactams via a [2+2] cycloaddition[40] could not observed, making
for an unusual selectivity. Crystals suitable for X-ray single crystal
structure analysis were gained by crystallization from DCM/
pentane at 4°C, confirming the structure (Figure 8).[28]
Figure 7. Solid state molecular structure of 7c.[28] Hydrogen atoms were omitted
for carity.
The carbene intermediate does not only attack the vinyl moiety
but also the double bond on the indene substructure, giving
intermediate VII. This polycycle eliminates HF while undergoing a
ring expansion. Similar halogenating ring expansions have been
studied by Volchok et al..[36] The resulting intermediate IX
rearranges to 7c via an intramolecular Alder-ene reaction
(Scheme 8).
Figure 8. Molecular structure of 8 in the crystal.[28] Hydrogen atoms were
omitted for clarity.
Conclusion
Scheme 8. Proposed mechanism for the formation of 7c.
Using only 0.7 eq. of CF3TMS gave
a mixture of 3c,
Within the framework of our investigation, we established a mild
novel synthesis of vinyl ethers from easy-to-make 1,5-diyne
systems and ketones acting as reagent and solvent. This method
utilizes aurated high energy species[12],[13] and can be considered
an otherwise difficult to access retrosynthetic disconnection.
Hence, this gold catalyzed transformation stands complementary
to established methods.[27],[16] The scope and limitations of this
transformation have been studied by modifying the backbone and
substituents on the alkynes. Overall thirteen novel vinyl ethers
have been isolated in moderate to good yields, ranging between
32% and 78%. Within these studies, we discovered an unreported
solvent controlled “switching” of the regioselectivity of a gold
catalyzed 6-endo-dig to a 5-endo-dig cyclisation starting from
1,5-diynes. So far, such transformation modes have been strictly
controlled by the substitution patterns of the starting material.
Hints were gathered, that the polarity of the solvent is the key to
this unusual selectivity, however hard evidence remains to be
found.
monocyclopropanated product and 7c as determined by GCMS.
While this ring expansion of indene has been previously reported,
this kind of reactivity on benzofulvenes has not been observed yet.
Literature-known rearrangements of fulvenes to arenes follow
harsh reaction conditions or require special substitution
patterns.[37]
Another compound class of considerable interest is the broad
family of sulfonamides, whose synthesis is a crucial point in
medical chemistry, as they appear in numerous biological active
compounds. In fact, amide formation is one of the most important
synthetic steps in the pharmaceutical industry.[38] To convert
6-(vinyloxy)fulvenes into this interesting functional group, 3m can
be left to react with CSI (Scheme 9).
H2N
S
O
N
O
O
O
S
O
Cl
O
Ph
Ph
1)
Ph
Ph
O
2), NaHSO3, NaOH, H2O
Et2O, -10°C
Furthermore, the previously unknown substructure of
6-(vinyloxy)fulvenes is introduced and briefly evaluated regarding
its chemistry. Mild and convenient functionalizations reveal a
large potential for further transformations and applications in
medicinal science. Fluorinated cyclopropanes and sulfonamides
3m
Scheme 9. Synthesis of amide 8 starting from 3m.
8
(76%)
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the respective, preferably dry, ketone (cdiyne = 150 µmol/ml) under air.
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kcal/mol in acetone in comparison to the not observed 6-endo-dig-cyclisation
via an aryl cation intermediate. In benzene the 6-endo-dig-cyclisation via an
aryl cation intermediate is favoured by 0.23 kcal/mol in comparison to the not
observed 5-endo-dig-cyclisation via a vinyl cation intermediate. These values
coincide with the observed selectivity, but the differences in energy are too low
to make for conclusive data. Please see SI for full data.
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Acknowledgements
D. M. Lustosa is grateful for a Science without Borders fellowship
of the Brazilian Council for Scientific and Technological
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Keywords: aryl cations • fulvene ethers • gold catalysis • vinyl
cations • vinyl ethers
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RESEARCH ARTICLE
Text for Table of Contents
Alexander Ahrens, Julia Schwarz, Danilo
M. Lustosa, Rahele Pourkaveh, Marvin
Hoffmann, Frank Rominger, Matthias
Rudolph, Andreas Dreuw, A. Stephen K.
Hashmi*
Page No. – Page No.
Synthesis of Fulvene Vinyl Ethers by
Gold Catalysis
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