Different Selectivities in the Insertions into C(sp2)?H Bonds: Benzofulvenes by Dual Gold Catalysis Competition Experiments

Article abstract of DOI:10.1002/chem.201801031

An unprecedented, often almost quantitative access to tricyclic aromatic compounds by dual gold catalysis was developed. This synthetic route expands the scope of benzofulvene derivatives through a C(sp²)?H bond insertion in easily available starting materials. The insertion takes place with an exclusive chemoselectivity with respect to the competing aromatic C?H positions. A bidirectional synthesis with two competing ortho-aryl C?H bonds in the selectivity-determining step also shows perfect selectivity; this result is explained by a computational investigation of the two conceivable intermediates. The intramolecular competition of two non-equivalent aryl C?H bonds with a benzylic methyl group also showed perfect selectivity.

Full text of DOI:10.1002/chem.201801031

A Journal of
Accepted Article
Title: Different Selectivities in the Insertions into C(sp2)-H Bonds -
Benzofulvenes by Dual Gold Catalysis Competition Experiments
Authors: Alex Plajer, Lukas Ahrens, Marcel Wieteck, Danilo M.
Lustosa, Rasool BabaAhmadi, Brian Yates, Alireza Ariafard,
Matthias Rudolph, Frank Rominger, and A. Stephen K.
Hashmi
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10.1002/chem.201801031
Chemistry - A European Journal
Different Selectivities in the Insertions into C(sp2)-H Bonds – Benzofulvenes by
Dual Gold Catalysis Competition Experiments**
Alex Plajer,[a] Lukas Ahrens,[a] Marcel Wieteck,[a] Danilo M. Lustosa,[a] Rasool
BabaAhmadi,[b] Brian Yates,[b] Alireza Ariafard,[b] Matthias Rudolph,[a] Frank
Rominger,[a] A. Stephen K. Hashmi*,[a],[c]
[a] Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg (Germany)
Fax:
(+49)-6221-54-4205;
E-mail:
hashmi@hashmi.de;
homepage:http://www.hashmi.de
[b] Dr. B. Yates, Dr. A. Ariafard
School of Physical Sciences (Chemistry)
University of Tasmania
Private Bag 75, Hobart TAS 7001 (Australia)
[c] Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah
21589, Saudi Arabia
[**] D. M. Lustosa was supported by the Brazilian Council for Scientific and
Technological Development (CNPq, Science without Borders Program, 2015–2018)
Keywords: dual gold catalysis, gold vinylidenes, C,H insertion, benzofulvenes,
chemoselectivity
Abstract: An unprecedented, often almost quantitative access to tricyclic aromatic
compounds by dual gold catalysis was developed. This synthetic route expands the
scope of benzofulvene derivatives through a C(sp2)-H bond insertion in easily available
starting materials. The insertion takes place with an exclusive chemoselectivity with
respect to the competing aromatic C-H positions. A bidirectional synthesis with two
competing ortho-aryl C,H bonds in the selectivity-determining step also shows perfect
selectivity; this result is explained by a computational investigation of the two
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conceivable intermediates. The intramolecular competition of two non-equivalent aryl-
C,H bond with a benzylic methyl group also showed perfect selectivity.
Introduction
Recently, the field of 1,5-diyne cyclizations by dual[1] gold catalysis[2] has developed
substantially.
The synthetic utility of this methodology was already demonstrated by the syntheses
of benzofulvenes,[1a,1c,1j] dibenzopentalenes,[1c,1m] benzocyclobutenes[1e] and various
annulated aromatic compounds that were derived from either intra- or intermolecular
C-H insertions[1b, 1o,1p] (Scheme 1). The insertion step is initated by an gold vinylidene
intermediate formed in situ by a 5-exo-dig cyclization, a species for which a derivate
[3]
has been recently characterized spectroscopically by Widenhoefer et al.
As an
alternative to the vinylidene intermediate, depending on the backbone and the
substitution pattern of the substrate, a 6-endo-dig cyclization can take place, leading
to digold-substituted carbene species as key intermediates.[1g,1h,1n] A subsequent C,H
insertion of these high energy intermediates enables the activation of unreactive sp2-
and sp3-C,H bonds.
Scheme 1. Scope of dual catalysis.
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Based on these principles, dual gold-catalyzed cyclizations represent a broadly
applicable, atom economical[4] and fast access to polycyclic frameworks under mild
conditions and with high yields. So far, catalytic approaches to benzofulvenes are
based on insertions into the C(sp3)-H bond of a distal terminal alkyl chain on one of the
alkynes.[1a,1d] We now considered a different synthetic strategy in which the
intermediate vinylidene is no longer annulated, but it forms the benzannulation in the
consecutive insertion step. The idea is based on our recent report on the insertion into
CH-bonds offered by substituents at the propargylic position of open-chained
substrates which possess one terminal alkyne (Scheme 2, upper part).[1l] For these
substrates no conformationally pre-orientated starting materials were needed; due to
the Thorpe-Ingold effect[5] these open-chained systems readily cyclized and the
intermediate vinylidene I was trapped by the substituent in propargylic position. For
these systems a good selectivity was achieved by using a simple methyl group, which
cannot undergo C,H insersion as a strained four-membered ring would be formed, as
“protecting group” at the internal alkyne. In order to implement the new, alternative
benzofulvene synthesis, we now applied related open-chained substrates of type 3a
(Scheme 2, lower part). In 3a a competing an equidistant sp2-CH-bond was offered by
via the arene moiety attached to the internal alkyne. This approach, presupposing a
chemoselective attack of the vinylidene species, facilitates an alternative
functionalization and represents a conceptionally new synthesis of benzofulvenes.
Scheme 2. Diyne cyclization by dual catalysis and envisioned C‐H insertion towards
benzofulvene 4a and possible byproduct 5.
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Results and Discussion
For our studies the test compound 3a was synthesized and subjected to 5 mol% IPr-
DAC-PF6 (DAC = dual activation catalyst)[1k] in toluene at 60°C. After 1 hour a clean
reaction delivered 4a in excellent yield and perfect selectivity, no byproduct could be
detected. The tricyclic structure and the two untouched germinal phenyl groups were
unambiguously confirmed by an X-ray single crystal structure analysis of 4a (Figure
1).[6]
Figure 1. Solid state molecular structure of 4a. Ellipsoids set at 50% probability.
Hydrogen atoms are omitted for clarity.
Next for the conversion of 3a a variation of the counter ion of the DAC was tested. In
contrast to our preceding investigation with aliphatic backbones,[1l] an influence of the
catalyst’s counter ion on the selectivity was observed. While catalysts with [NTf2]- and
[PF6]- showed no byproducts, [BF4]- and [OTf]- gave significant amounts of byproduct.
Treatment with DAC-SbF6 yielded a completely different and fluorescent product,
which was very sensitive and could not be isolated. Since DAC-PF6 showed higher
reaction rates than the corresponding catalysts with [NTf2]- counter anions, DAC-PF6
was chosen for the following reactions. The reaction temperature of 60 °C is lower than
the temperature needed for the cyclization of substrates of type 1 (80 °C were
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necessary for these compounds). Scheme 3 represents the optimized reaction
conditions.
Scheme 3. Conversion of the diyne 3a under the optimized conditions.
In order to evaluate the scope of the concept, various starting diynes were synthesized,
following a strategy depicted in Scheme 4. Starting point for the synthesis was the
generation of a tertiary alcohol 6 by the two-fold Grignard addition to ethyl formate. The
alcohol was consecutively transformed to the corresponding nitrile 7 by treatment with
trimethylsilyl cyanide via indium(III) bromide catalysis.[7] Propargylation was followed
by a Sonogashira coupling with the additional aryl moiety. Then the nitrile group in 9
was transformed to the terminal alkyne 10 by reduction to the corresponding aldehyde
with DIBAL-H and subsequent treatment with the Bestmann-Ohira reagent.
Scheme 4. General synthetic route for the preparation of the diynes 3.
A variety of starting materials was generated in this fashion and then converted to the
benzofulvene derivatives. Table 1 summarizes the scope of the catalysis reaction.
Overall, up to 99% yield can be obtained with both electron-donating and electron-
withdrawing substituents on each of the aromatic moieties attached to the starting
diyne systems. The reaction appears to be resilient with respect to electronic
influences. Neither substituents on the phenyl groups in the tether nor in the aryl moiety
on the alkyne showed a definite trend with respect to the yield. In agreement with
previous results, higher reaction rates were observed when the aryl group bearing the
attacked C(sp2)-H bond was functionalized with electron-donating substituents. It is
worth mentioning, that in no case a competing insertion via the arene in propargylic
position took place. This was even not the case for electron-rich moieties at the
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propargylic position in combination which electron-deficient substituents at the internal
alkyne part (products 4i, 4o, 4q, 4t, 4u).
Table 1. Scope of the synthesis of compounds 4.
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Following this route all benzofulvenes were obtained as the only products in good to
very good yields. Compared to the existing approaches, the presented synthetic route
enables a range of new substitution patterns.
In order to further examine the synthetic possibilities, a potential substrate for a
bidirectional reaction was synthesized (Scheme 5). Using 1,4-diiodobenzene two diyne
systems in 3v were connected.
After the first cyclization, again an intramolecular competition experiment of the two
non-equivalent ortho-C,H bonds of the central benzene core is possible. Treatment of
the tetrayne system with the gold catalyst delivered the corresponding polycyclic
product that precipitated in high yield. The high selectivity of the reaction is remarkable
as the formation of two different products 4v and 4v´ should be possible. As a first
structural proof, a NOESY NMR experiment was conducted. It shows cross peaks for
both of the fulvene protons Ha and Hb to the central aromatic proton Hc, which clarifies
that only the linear annulated product is formed in the reaction. Not even traces of the
angular product (here only one NOESY cross peak would be visible) were obtained.
Scheme 5. Bidirectional variant yielding a pentacyclic compound 4v.
Finally, efforts to grow single crystals of 4v were successful. The molecular structure
is shown in Figure 2, it confirms the linear annulation.
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Figure 2. Solid state molecular structure of 4v. Ellipsoids set at 50% probability.
Hydrogen atoms are omitted for clarity.
Furthermore, substrate 3w, offering three additional benzylic C(sp3)-H bonds as
potentially competing insertion positions, was synthesized. An alternative insertion into
the corresponding vinylidene species would deliver a six-membered cycle 11 (Scheme
6). Despite this additional possibility 90% yield of the C(sp2)-H insertion product 4w
(forming the five-membered system) was obtained as single product. Consequently
the methyl group has no apparent influence on the reaction.
Scheme 6. Intramolecular competition experiment with substrate 3w.
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Finally, the diaryl substitutents in propargylic position were replaced by a saturated
cyclohexyl framework (Scheme 7, 3x). Indeed, the spirocyclic benzofulvene derivate
4x was formed, but despite the increased reaction temperatures and times and a
catalyst adaption, the yield of the reaction was only moderate. This behavior probably
is caused by the reduced steric demand of the cyclohexyl backbone resulting in a
decreased Thorpe-Ingold effect which influences the efficiency of the initial cyclization
to the spirocyclic vinylidene species. Due to it’s conformational restrictions the
cyclohexyl substituent does not place C,H bonds close to the vinylidene carbon.
Scheme 7. Synthesis of spirocyclic compound 3x.
Based on prior mechanistic studies conducted for dual gold-catalyzed reactions.[1] we
propose[8] a catalytic scenario as displayed in Scheme 8. The reaction is initiated by
the transfer of the two gold fragments from the dual activation catalyst under loss of
propyne. The ,-activated starting material then undergoes a 5-endo-dig cyclization
forming vinylidene III, which then is attacked by the in-plain phenyl group. After
formation of the gem-diaurated species V a transfer of the two gold atoms onto the
next starting material under liberation of the product closes the catalytic cycle.[9]
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Scheme 8. Catalytic cycle for the formation of 4a.
In the formation of 4a the step from intermediate III to intermediate IV is selectivity-
determining. This positional selectivity is shown in Scheme 9. The insertion into one of
the four symmetry equivalent C-Ha bonds would lead to intermediate IVa-int via
transition state IIIa-TS. On the other hand, an insertion into one of the two symmetry
equivalent C-Hb bonds will provide intermediate VI-int via IIIb-TS. The difference is
that the arene bearing Ha is connected to the gold vinylidene by an sp3-carbon, while
Hb is connected by an sp2-carbon. A computational study revealed that IIIa-TS is 3.5
kcal/mol higher than IIIb-TS, which perfectly explains the experimentally observed
selectivity. Furthermore, intermediate IVa-int is 9.8 kcal/mol above IV-int., which is in
perfect accord with the more extended -system for the delocalization of the positive
charge in IV-int. Ultimately, IV-int provides 4a while IVa-int leads to 5, the overall
reaction free energies for both pathways (-53.3 kcal/mol, -53.0 kcal/mol) are
comparable within the error of the computational study (Scheme 10).
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Scheme 9. Computational study of the selectivity-determining step in the anellation
leading to IV-int.
C,Ha
insertion product
C,Hb
insertion product
Ha
Ha
Hb
Hb
Ha
Hb
4a
3a
0.0 kcal/mol
5
-53.0
-52.3
Scheme 10. Overall reaction free energy of the two competing pathways.
In order to explain the observed regioselectivity of the bidirectional synthesis, leading
to 4v but not to the isomer 4v’, we conducted a computational study focusing on the
selectivity-determining step after the first cyclization on one side is already finished and
the second cyclization on the other side in the C-C bond-forming step following the
formation of intermediate Int0_L has two possibilities (Scheme 9).
This computational study clearly revealed that the transition state TS1_L and the
subsequent intermediate Int1_L ultimately leading to the not-observed 4v’ are
significantly higher in energy than the corresponding TS2_L and the intermediate
Int2_L, the later indeed leading to the observed product 4v.
Analyzing the geometry of the two structures of TS1_L and TS2_L (Figure 3), it
becomes obvious that the additional 7.6 kcal/mol in TS1_L mainly are caused by a
repulsive interaction of the gold complex with one of the phenyl rings on the other end
of the molecule, on the end which has formed the benzofulvene substructure in the
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first cylization (in Scheme 11 on the right top side of the molecules, in Figure 3 the
steric interaction in the left structure).
Scheme 11. Computational study of the selectivity-determining step in the anellation
leading to 4v.
Figure 3. Comparison of the geometries of TS1_L and TS2_L.
Conclusion
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A novel synthetic approach to previously inaccessible benzofulvene derivates through
a selective dual gold-catalyzed 1,5-diyne cyclization was achieved. A remarkable
chemoselectivity concerning the C-H activation step leads to the formation of the
products in high yields without the formation of byproducts derived from competing CH-
insertions. The cyclization occurs under mild reaction conditions, tolerates a broad
range of aromatic substituents and even quantitative yields can be obtained by
uncomplicated purification methods. By following this methodology complex aromatic
systems can be synthesized in an overall short synthetic sequence. In the future this
will be an ideal starting point for new extended -systems for material science.
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