Gold vinylidene complexes: Intermolecular C(sp3)-H insertions and cyclopropanations pathways

Full text of DOI:10.1002/anie.201204015

Angewandte
Chemie
DOI: 10.1002/anie.201204015
Dual Activation
3
ꢀ
Gold Vinylidene Complexes: Intermolecular C(sp ) H Insertions and
Cyclopropanations Pathways**
A. Stephen K. Hashmi,* Marcel Wieteck, Ingo Braun, Matthias Rudolph, and Frank Rominger
The most common reactivity pattern for gold-catalyzed
transformations is the inter- or intramolecular attack of
a nucleophile on a multiple bond which is activated by p-
coordination to a gold catalyst. This situation opens up an
immense spectrum of useful transformations for organic
chemists.[1] Early this year, Zhangꢀs group and our group
independently reported on a new activation mode which
comprises a dual role of the gold catalyst (Scheme 1).[2] While
the vinylidene intermediate with the solvent benzene was
possible. These results encouraged us to explore further
possible transformations of intermediate II in intermolecular
reactions. The results of these studies are summarized herein.
The ability of vinylidene intermediates to insert intra-
3
ꢀ
moleculary into C(sp ) H bonds was already exploited by
Zhangꢀs group and our group. As a consequence, first
experiments were conducted to investigate the possibility of
3
ꢀ
intermolecular C(sp ) H bond insertions. To date, for such
3
ꢀ
unactivated alkanes, an intermolecular C(sp ) H insertion is
unknown for any other gold species and its occurrence would
demonstrate the immense reactivity of gold(I) vinylidene
intermediates.
As a test reaction we used diyne 4a which had already
been used as substrate for the intermolecular hydroarylation
reaction.[2b] To avoid regioselectivity problems, cycloalkanes
ꢀ
were used for the possible C H insertion. In analogy to the
hydroarylating cyclization reaction, the cycloalkanes were
used as the solvent and comparable reaction conditions were
applied (Scheme 2), IPrAuPh was used as an additive. A fast
ligand exchange of this organogold compound with the
Scheme 1. First examples of rearrangements involving vinylidene gold
complexes.
one molecule of gold catalyst activates an alkyne by the
established p-activation mode, a second gold complex [LAu+]
activates a terminal triple bond by formation of a gold(I)
acetylide, which changes the whole reaction pathway. Highly
reactive digold intermediates II with a gold(I) vinylidene
substructure are formed and open up entirely new reaction
pathways (Scheme 1). So far, fulvene derivatives 1[2a,d] and 2[2c]
were accessible by intramolecular sp3 and sp2 insertion
pathways. Furthermore, the conversion of bis-terminal
alkynes selectively delivered the b-substituted naphthalene
product 3.[2b] In this case even an intermolecular reaction of
3
ꢀ
Scheme 2. Intermolecular C(sp ) H insertion reactions.
starting material initiates the dual catalysis cycle by forming
an acetylide. To our delight, a conversion of the starting diyne
could be monitored by thin layer chromatography, but
reaction rates turned out to be much slower than for the
benzene addition reaction. Nevertheless, we were able to
obtain the C(sp ) H bond insertion products for three
different cycloalkanes (Scheme 2, compounds 5aa–ac). The
relatively low yields for this type of reaction are because of
a slow decomposition of the starting diyne at 808C in
combination with the long reaction times.[3] For the product
obtained with cyclohexane, crystals suitable for an X-ray
crystal structure analysis were obtained.[4] It confirms the
formation of the naphthalene skeleton and in perfect analogy
with the hydroarylating reaction, the substituent is on the b-
[*] Prof. Dr. A. S. K. Hashmi, M. Sc. M. Wieteck, Dr. I. Braun,
Dr. M. Rudolph, Dr. F. Rominger+
Organisch-Chemisches Institut
3
ꢀ
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
[+] Crystallographic investigation.
[**] We thank Umicore AG & Co. KG for the generous donation of gold
salts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204015.
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Table 1: Gold-catalyzed synthesis of cyclobutene derivatives 7a.
position. It is noteworthy that unlike in the case of the
ꢀ
intramolecular C H insertion reactions, no benzofulvene
structures are obtained. Instead ring expansion and formation
of the naphthalene skeleton takes place. The lack of a ring
expansion in the case of fulvenes 1 and 2 (intramolecular
reaction) can be explained by the strained cyclobutane
derivatives that would be the final products.
Next, we investigated alkenes as more-reactive partners.
As cyclopropanation by gold carbenes is a frequently
observed reactivity pattern,[5] we considered that goldvinyli-
dene II might show comparable reactivity, and thus be
a synthon for an alkylidene carbene.[6]
Entry
1
Olefin
Product (yield)
7aa
(64%)
6a
6b
6c
6d
An initial experiment with diyne substrate 4a and
a mixture of 5 mol% IPrAuNTf2 and 10 mol% IPrAuPh or
IPrAuMe (as an additive for acetylide formation)[2b] delivered
quantitative conversion of the starting material in cyclo-
hexene as solvent (ca. 100 mmolmLꢀ1). The preparative scale
of the reaction delivered the product in 64% yield (Table 1,
entry 1). Fortunately, we were able to obtain crystals of 7aa
suitable for an X-ray crystal structure analysis.[4] Product 7aa
shows a naphthyl scaffold anellated to a cyclobutene ring at
the a,b-position of the naphthalene core. There are only a few
synthetic routes to such structures, which need drastic
reaction conditions.[7] The cis-diastereomer was obtained
exclusively. Encouraged by this initial experiment, we
explored the reaction of diyne 4a with different alkenes as
solvent (ca. 100 mmolmLꢀ1). 1,4-Cyclohexadiene delivered
benzocyclobutene-type products, too (entry 2). Owing to the
excess of alkene, not even traces of the product of a two-fold
addition could be detected. Norbornene also turned out to be
a suitable alkene. In addition, the yield of the reaction was
very good (entry 3). In this case, the corresponding diene
norbornadiene did not deliver similar results, rather unex-
pectedly the yield dropped significantly (entry 4). Larger
cycloalkenes were also tolerated, which was demonstrated by
cis-cyclooctene (entry 5) and 1,5-cyclooctadiene (entry 6).
Both reactions smoothly delivered the interesting bicyclo-
[6.2.0]decane scaffolds in high yields.
7ab
(65%)
2
3
4
7ac
(81%)
7ad
(41%)
7ae
(84%)
5
6
7
6e
6 f
6g
7af
(71%)
7ag
(64%)
Next we applied non-cyclic alkenes as starting materials.
To our surprise, unsymmetrical 1-heptene only delivered one
single product albeit in only moderate yield (entry 7). The
NOE-NMR spectrum of compound 7ag, showing cross-peaks
of the protons of the methylene group directly bound to the
cyclobutene ring and an aromatic singlet. Based on the
proximity of these groups, only the structure shown for 7ag is
possible. To further investigate the stereochemical course of
the reaction, both trans and cis-3-hexene were used as
reactants (entries 8 and 9). The reaction turned out to be
highly stereoselective and each of the products obtained was
7ah
(49%)
8
9
6h
6i
7ai
(28%)
1
diastereomerically pure (even in the H NMR spectra of the
crude products no traces of the other diastereoisomer were
detectable). The double bond configurations of the starting
alkenes were cleanly translated into the final product. The
Our next aim was to gain further insight into the reaction
mechanism. A first experiment was performed with substrate
[D2]-4a bearing deuterium labels at both of the terminal
positions of the alkyne (Scheme 3). In the product, a high
degree of isotopic labeling was observed for the aromatic
hydrogen atom next to the ring fusion point. In addition more
than 50% deuterium labeling could be detected at the second
aromatic proton that is generated after cyclization. The
deuterium labeling of the product shows a close relationship
3
configuration was assigned by the J-coupling constants in
proton NMR spectrum (cis: 10.5 Hz vs. trans: 1.4 Hz). Further
proof was provided by the X-ray crystal structure analysis of
compound 7ai.[4] These results exclude a step-wise process
with cationic intermediates for the intermolecular attack at
the olefin.
2
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The starting material 8a was consumed within seconds and
a crystalline solid could be isolated. To assign the product
structure definitely, an X-ray crystal structure analysis was
conducted (Figure 1). In complete accordance to our recently
published results on dual gold catalysis,[2b–d] a gem-diaurated
species 11aa was formed (Scheme 5). The structural core of
Scheme 3. Isotopic labeling experiment.
to our previously reported hydroarylating aromatization
product and thus is evidence for a related reaction pathway.[2b]
Slightly lower isotopic labeling might be influenced from
traces of acid in the absence of basic additives (these were
used for the labeling experiments of the hydroarylating
reaction).
Recently, Echavarren and co-workers reported on a gold-
catalyzed intermolecular [2+2] cycloaddition of alkynes with
alkenes.[8] To explore if a related mechanism (i.e. an initial
[2+2] cycloaddition followed by enyne cyclization with the
second alkyne moiety) is relevant for our reaction, a control
experiment using the original conditions of Echavarren et al.
was conducted (CH2Cl2, cyclohexene/alkyne 2:1, 3 mol% tert-
butyl XPhosAuSbF6, room temperature), but no conversion of
diyne substrate 4a was observed (not even the formation of
a [2+2] cycloaddition product took place). In addition, we
tested the reaction of phenylacetylene in cyclohexene using
our catalyst system. Even after 3 days at 808C no reaction was
observed. To evaluate if a cyclobutene 10 might be a possible
intermediate, we synthesized this species, starting from ortho-
alkynylhaloarenes 9 (Scheme 4). It is noteworthy that for
Figure 1. Crystal structure of 11aa (H atom omitted, thermal ellipsoids
set at 50% probability).
Scheme 5. Isolation of the diaurated benzocyclobutene 11aa.
the final product was already present, in addition two gold
atoms are connected to the d-position of the naphthalene
unit. As these atoms originate from electrophilic attack at the
mono-aurated derivatives,[9] from our preceding work[2b–d] it is
clear that in the last stage of the reaction the mono-gold
derivative of compound 11aa should be an intermediate. In
perfect analogy to our previously reported related gem-
diaurated species, this compound was catalytically active for
the transformation (3 mol% 11aa for the conversion of 4a
into 7aa; isolated in 62% yield).
Scheme 4. Control experiment with cyclobutene 10.
Our next experiments addressed the positional selectivity
of the alkene incorporation. We prepared the unsymmetri-
cally substituted diyne 4b and subjected it to a catalytic
amount of our catalyst combination in cyclohexene
(Scheme 6). After work-up, a mixture of two regioisomeric
products was obtained, favoring 7ba-B (2:1). We assume that
the difference in pKa values triggers the selectivity. The
methoxy group para to the alkyne should disfavor its acetylide
formation, thus it is likely that the cyclohexene unit is
incorporated at the other acetylide moiety. Additional proof
for this assumption was obtained with the unsymmetrically
substituted mono-acetylide 8b (for the synthesis of 8b see
Supporting Information). The results of the reaction under
catalytic conditions revealed a high 9:1 positional selectivity
and furthermore regioisomer 7ba-A was favored in this case.
The positional selectivity of the cyclohexene towards the gold
alkynes 9 Echavarrenꢀs cyclobutene synthesis did not work for
cyclohexene (which readily reacts with our diyne substrates).
Instead we used tetramethyethylene (an alkene which turned
out to be unreactive with our diyne systems). We then
converted this possible intermediate under our conditions. As
result, only an unselective reaction was detected. Together
with the mentioned orthogonal reactivity of the alkenes, this
clearly excludes a [2+2] mechanism in the first reaction step.
Thus the mechanism based on the dual-activation scenario
seems to operate. For this reaction mode, the initial step
would involve a gold acetylide as the reactive species. To
check the reactivity of a gold acetylide, we prepared gold
acetylide 8a from diyne 4a and IPrAuCl (Et3N/CH2Cl2, room
temperature, 92%) and subjected it to stoichiometric
amounts of activated catalyst in cyclohexene (Scheme 5).
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tization reaction.[2b] In the next step, a stereospecific cyclo-
propanation takes place, which indicates an alkylidene
carbenoid reactivity of the vinylidene (if an electrophilic
attack at the olefin would occur, involving an open-chained
carbenium ion, the reaction should not be stereospecific for
acyclic cis- and trans-alkenes). The methylenecyclopropane
IV then undergoes a gold-catalyzed ring-expansion cascade.
The rearrangement of methylenecyclopropanes to cyclobu-
tenes catalyzed by platinum[11] or palladium[12] were recently
published. Upon coordination of the gold to the highly
activated double bond of III, a cyclobutane carbene inter-
mediate V is formed, which after a shift of the vinyl group
delivers the molecular skeleton of the product. Simple
elimination of the cationic gold catalyst [Au]+ from VI then
regenerates the aromatic ring. Finally, the catalytic cycle is
closed by a catalyst transfer of mono-aurated compound VII
(which is in equilibrium with gem-diaurated species 11) onto
the starting diyne 4 under regeneration of the s-activated
starting material 8.
In conclusion, based on highly reactive gold vinylidene
species two new intermolecular reaction pathways were
developed. Even normally inactive species, such as cyclo-
alkanes react with these high-energy intermediates. Further-
more, these species might be regarded as alkylidene carbene
synthons, species that are usually generated under harsh
reaction conditions and by using toxic reagents. The alkene
incorporation reaction presented herein once more demon-
strates the advantages of dual gold catalysis. Complex
polycyclic aromatic systems are available in only one reaction
step from simple diyne precursors. By using the powerful
reactivity of gold vinyli-
Scheme 6. Positional selectivity of the alkene incorporation.
acetylide also excludes the alkyne/alkene [2+2] cycloaddition
pathway. Previous mechanistic investigations by Corma[10]
have revealed that gold acetylides are unreactive for the
cycloaddition which is confirmed by the non-reactivity of IPr-
substituted phenylacetylide under our reaction conditions.
The mechanistic investigation clearly indicates a reaction
pathway which shows a close relationship to previously
reported dual gold-catalyzed reactions. Our mechanistic
rationale is depicted in Scheme 7. The catalytic cycle is
initiated by ligand exchange with the phenyl gold complex
that is added. After the formation of the gold acetylide, the
attack of the b-carbon at the p-activated alkyne leads to the
formation of highly active vinylidene intermediate (I!II).
These first steps are identical to the hydroarylating aroma-
denes, completely new reac-
tions will become available.
Received: May 23, 2012
Revised: July 11, 2012
Published online: && &&,
&&&&
Keywords: benzocyclobu-
.
ꢀ
tenes · C H activation ·
dual activation · gold ·
vinylidenes
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4
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Communications
Dual Activation
A. S. K. Hashmi,* M. Wieteck, I. Braun,
M. Rudolph, F. Rominger
&&&& — &&&&
Gold Vinylidene Complexes:
3
ꢀ
Intermolecular C(sp ) H Insertions and
Cyclopropanations Pathways
Highly reactive gold vinylidene species
benes. Initiated by cyclopropanation of
the vinylidene species/alkylidene carben-
oide, cyclobutene derivatives are formed
in a diastereoselective fashion by a ring-
enlargement cascade in only one step.
3
ꢀ
are used for intermolecular C(sp ) H
insertions into unactivated alkanes (see
scheme). In addition, they can be
regarded as synthons for alkylidene car-
6
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