Non-Innocent Behavior of Substrate Backbone Esters in Metal-Catalyzed Carbocyclizations and Friedel-Crafts Reactions of Enynes and Arenynes

Article abstract of DOI:10.1021/acs.joc.5b02052

On the basis of DFT computations and experimental results, we show that the presence of the ester group in the backbone of organic substrates can influence the mechanism of metal-catalyzed carbocyclization reactions. The non-innocent role of the ester fun

Full text of DOI:10.1021/acs.joc.5b02052

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Article
On the Non-Innocent Behavior of Substrate Backbone
Esters in Metal-Catalyzed Carbocyclizations and
Friedel-Crafts Reactions of Enynes and Arenynes
Bastien Michelet, Guillaume Thiery, Christophe Bour, and Vincent Gandon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02052 • Publication Date (Web): 08 Oct 2015
Downloaded from http://pubs.acs.org on October 12, 2015
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On the Non-Innocent Behavior of Substrate Backbone Esters in Metal-Catalyzed
Carbocyclizations and Friedel-Crafts Reactions of Enynes and Arenynes
†
†
†
†,§,
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Bastien Michelet, Guillaume Thiery, Christophe Bour, and Vincent Gandon *
†
ICMMO (UMR CNRS 8182), Université Paris-Sud, Bâtiment 420, 91405 Orsay cedex, France
§
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
vincent.gandon@u-psud.fr
Abstract: On the basis of DFT computations and experimental results, we show that the presence of
the ester group in the backbone of organic substrates can influence the mechanism of metalꢀcatalyzed
carbocyclization reactions. The nonꢀinnocent role of the ester functionality in lowering the activation
barrier of the key step of the galliumꢀ and indiumꢀcatalyzed cycloisomerization of 1,6ꢀenynes is
revealed. In the case of the galliumꢀcatalyzed hydroarylation of arenynes, the esters in the tether can
deprotonate the Wheland intermediate, thus avoiding more energetically demanding [1,3]ꢀ or
[
1,2]/[1,2]ꢀH shifts. As for the galliumꢀcatalyzed FriedelꢀCrafts alkylation, an unusual concerted S Ar
E
mechanism involving the esters has been calculated. Lastly, computations evidence that the ester
group of methyl propiolates enables a divergent mechanism in the platinumꢀcatalyzed intramolecular
hydroarylation.
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1- Introduction.
The synthesis of polyunsaturated substrates for metalꢀcatalyzed reactions such as
cycloisomerizations, metatheses, cycloadditions, etc., typically starts from an active methylene
compound which is sequentially functionalized under basic conditions to form enynes, diynes, dienes,
arenynes, etc. (Scheme 1). The electronꢀwithdrawing groups of the starting active methylene
compound usually remain as part of the tether between the unsaturated CꢀC bonds and their presence
is wellꢀtolerated in most cases.
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Scheme 1. Synthesis of Polyunsaturated Precursors from Active Methylene Compounds
For instance, countless substrates for metalꢀcatalyzed reactions have been straightforwardly
constructed by malonic ester synthesis (Chart 1).
Chart 1. Examples of Substrates Used in Metal Catalysis Displaying a gem-Diester in the
Tether
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The ease and versatility of this synthetic approach is not its only advantage. It is also wellꢀ
established that the gemꢀdisubstitution of the tether accelerates cyclization steps by ThorpeꢀIngold or
1
reactive rotamer effects. One could also envisage that the presence of functional groups in the tether
influences the elementary steps of a catalytic cycle in other ways. As they are at the same time
electronꢀwithdrawing groups and electron donors though their heteroatom lone pairs, they could
possibly exert long range inductive effects, stabilize charges, establish stabilizing nonꢀcovalent
interactions, capture protons, etc. Some of these aspects are wellꢀknown in biology or sugar chemistry
for instance, but they have been much less studied in the context of metalꢀcatalyzed reactions. On the
basis of DFT calculations, we show in this article that the gemꢀdiester in the tether can provide more
than a mere kinetic gemꢀdisubstituent effect in gallium(III)ꢀ and indium(III)ꢀcatalyzed C–C bond
forming reactions by serving as proton shuttle. In particular, an overlooked baseꢀeffect in Friedelꢀ
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E
Crafts reactions leading to stepwise or concerted S Ar pathways is discussed. We finally broaden the
discussion to the case of a single ester substituent located at the reactive alkyne unit of a substrate
under platinum(II) catalysis, and show that its presence can set up a new mechanistic scenario.
2- Results and Discussion
2.1- Ga(III)- and In(III)-Catalyzed Cycloisomerization of 1,6-Enynes
The metalꢀcatalyzed cycloisomerization of enynes and related compounds is a wellꢀestablished
2
strategy for the rapid increase of the molecular complexity from simple substrates. While a variety of
transition metal complexes can be used as catalysts for this reaction, simple salts derived from
3
polarizable main group elements are also efficient, notably gallium and indium halides. In this
section, we briefly reinvestigate part of a previously reported computational study in which the
structure of the enynes has been simplified by removing the gemꢀdisubstituent in the tethers.
In a series of recent papers, Yu et al used a combined theoretical and experimental approach to
4
identify the real catalytic species in GaX
3
ꢀ and InX
3
ꢀcatalyzed cycloisomerization of 1,6ꢀenynes. A
large body of their work relies on the reactivity of the gemꢀdiester tethered 1,6ꢀenyne 1 which was
previously shown by Miyanahana and Chatani to transform into the 1,4ꢀdiene 2 (E/Z mixture)
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exclusively in the presence of a catalytic amount of InCl , and not into the conjugated diene 3 (Scheme
5
2). Starting from the postulate that almost all catalysts give conjugated dienes with 1,6ꢀenynes except
InCl , Yu et al decided to study this reaction in detail so as to elucidate the origin of this peculiarity.
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The formation of 2 as a sole product could be reproduced with GaCl
3 3 3 3
, GaBr , InBr , InI , as well as
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with InCl /AgY mixtures (Y = SbF , BF , OTf, OCOCF ). The fluorene derivative 4 was also tested
3
6
4
3
and gave rise to the nonꢀconjugated product 5 with InCl as catalyst.
3
Scheme 2. Ga(III)- and In(III)-Catalyzed Cycloisomerization of Enynes 1 and 4
MX3
E
E
E
E
E
E
+
or MX3/AgY
1
2
3 (not formed)
E = CO2Me or CO2Et
M = In, Ga
X = Cl, Br, I
Y = SbF6, BF4, OTf, OCOCF3
InCl3
4
5
A neutral and a cationic pathway were considered to account for the selective formation of the nonꢀ
conjugated diene. A simplified overview of the mechanism limited to the most stable transꢀisomers of
D, E, H, and I is shown in Scheme 3. In the neutral pathway, enyne 1 forms complex A after
coordination of MX to the C≡C bond. Nucleophilic attack of the C=C bond provides the nonꢀclassical
3
carbocationic species B (depicted here as a chosen resonance form instead of the more abstruse
3
b
resonance hybrid), which then rearranges into the key intermediate C. The latter is the precursor of
the isolated product after selective [1,2]ꢀH migration of Hb (see complex D). That of Ha on the other
hand furnishes the unobserved conjugated product (see complex E).
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Scheme 3. Possible Mechanistic Pathways of the Ga(III)- and In(III)-Catalyzed
Cycloisomerization of Enyne 1
neutral pathway
X3M
Hb
Ha
MX3
MX3
Hb
MX3
Ha
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E
E
E
E
E
E
E
E
E
E
+
MX3
Hb
Ha
B
C
D
E
A
(
via 1,2-Hb shift)
(via 1,2-Ha shift)
MX3
OR
Hb
Ha
Hb
Hb
Ha
O
O
MX4-
E
E
E
E
E
E
+
X M
+
2
MX2
Ha
+
M
+
OR
M
X2
X2
F
G
H
I
cationic pathway
In the papers of Yu et al, calculations were carried out using the B3LYP functional, the
LANL2DZ+ECP basis set for In or Ga, the 6ꢀ31G(d) basis set for other elements (noted BS1 in Table
1
). On the basis of these DFT computations, the neutral pathway was ruled out. For instance, with
6
3 3 3
GaCl , calculations predict the wrong isomer E (see TSa-GaCl vs TSb-GaCl in Table 1, Entry 1).
The migration of Ha through TSa-GaCl would require 7.7 kcal/mol of free energy of activation while
3
3
that of Hb through TSb-GaCl would require 9.7 kcal/mol. We have reproduced these calculations at a
slightly different level of theory and reached the same conclusions (Entry 2, B3LYP/6ꢀ31G(d) for all
atoms (BS2)).
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Table 1. Free Energies of Activation (kcal/mol) of the Key Step of the Ga(III)-Catalyzed
Cycloisomerization of a Model 1,6-Enyne
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[
a]
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Entry
Theory Level
B3LYP/BS1
B3LYP/BS2
TSa-GaCl3
TSb-GaCl3
9.7
TSa-GaCl2
TSb-GaCl2
1
2
3
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9.1
9.0
8.3
6.4
4.4
5.2
3.0
1.9
10.8
M06ꢀ2X/BS3
9.6
[
a] BS1: LANL2DZ+ECP (Ga), 6ꢀ31G(d) (other elements), values of Entry 1 taken from the
Supporting Information of Ref 4c; BS2: 6ꢀ31G(d) (all elements); BS3: 6ꢀ311+G(d,p) (all elements).
A cationic scenario was then envisaged by Yu et al. They suggested that MX salts could react with
3
+
+
the solvent or the substrate to form MX
2
ions. An ion peak corresponding to [InCl
2
+2] could be
, enyne 1, and
is coordinated to
detected by ESIꢀHRMS analysis of a reaction mixture comprising 150 mol% of InCl
3
+
acetonitrile. The proposed structure corresponds to F in Scheme 3, in which MX
2
the ester groups of the tether of the enyne. However, acetonitrile is a solvent in which the reaction
4
a,7
+
2
cannot occur catalytically. Nevertheless, the possibility that MX could be the actual active species
+
was checked computationally by Yu et al. With GaCl
2
instead of GaCl
3
, the computations predicted
+
the experimentally observed nonꢀconjugated product as the preferred one (see TSa-GaCl
2
vs TSb-
+
GaCl
2
in Table 1, Entry 1). Again, we reached the same conclusions with BS2 (Entry 2). It was
suggested that the migration of Ha or Hb is encouraged by the electronic effect of the nearby
cyclopentene or methyl group. Since the cyclopentene is electronꢀricher, the migration of Ha should be
+
always favored, as with GaCl for instance. Yet, since GaCl2 displays two vacant orbitals instead of
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one in GaCl
3
, complexation of the C=C bond in the key intermediate becomes possible. This electron
depletion renders the terminal methyl group electronꢀricher, hence the preferred migration of Hb with
+
GaCl .
2
Yu et al now recommend the use of 1,6ꢀenynes as mechanistic probes to identify the real active
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4
c
species when GaX
3
or InX
3
salts are used as catalysts. If the reaction of 1 gives 2, then the active
+
+
species should be GaX or InX , and not GaX or InX . On the other hand, if the conjugated product
2
2
3
3
3
is obtained, then only the neutral pathway could explain its formation. Our research group has
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specialized in the use of neutral and cationic gallium and indium complexes in molecular catalysis. In
+
ꢀ
particular, we have developed the synthesis of complexes of type [IPr·MX ] [Y] (M = Ga, In; X = Cl,
2
Br, I; IPr = 1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolꢀ2ꢀylidene; Y = weakly coordinating anion). These
3
complexes can be isolated or generated in situ from IPr·MX and AgY. Since they display a single
coordination site, we reasoned that they should be able to imitate the behavior of monocoordinating
transition metal fragments and yield the conjugated product. Surprizingly, these species also gave rise
to 2 selectively from 1 (Table 2, Entries 1 and 2). After realizing that actually no report mentioned the
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formation of 2 or 3 by transition metalꢀcatalyzed cycloisomerization of 1, we tested it under Au(I)
1
0
+
+
2 3
catalysis and obtained again product 2 (Entry 3). However, with IPr·MX or Ph PAu fragments, the
coordination of the cyclopentene moiety to the metal center is unlikely.
Table 2. Ga(III)-, In(III)-, and Au(I)-Catalyzed Cycloisomerization of Enyne 1
[
b]
Entry
Catalyst
T [°C] t [h]
E : Z[a]
8 : 1
Yield
[c]
1
2
3
[IPr·GaCl ][Al(pftb) ]
80
80
20
4
2
1
32 (97)
42 (92)
50 (99)
2
4
[c]
[IPr·InBr
2
][Al(pftb)
4
]
4 : 1
[d]
[Ph
3
PAu][SbF
6
]
4 : 1
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[
a] Determined by GLC analysis. [b] Corrected yield of 2 admixed with some unreacted 1, conversion
1
1
3 4
are indicated in parentheses. [c] Generated in situ from IPr·MX (5 mol%) and [Ag][Al(pftb) ] (7
mol%); [d] Generated in situ from Ph PAuCl (5 mol%) and AgSbF (7 mol%).
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To address this discrepancy, we decided to test a different level of theory and then to take the gemꢀ
diester substitution into account. It is wellꢀestablished that while the B3LYP functional usually lead to
12
reliable geometries, better energies can be obtained with the Minnesota series of functionals. Among
13
them, the M06ꢀ2X performs very well for main group chemistry and nonꢀcovalent interactions. The
free energies shown in Table 1, Entry 3, have been obtained at the M06ꢀ2X/6ꢀ311+G(d,p) level. While
+
the preference for the nonꢀconjugated product remains clear with GaCl
2
, it is no longer obvious that
GaCl
3
would encourage the selective formation of the conjugated one, as the formation of products is
expected to take place at very similar energy costs. Thus, the choice in the level of theory seems
critical.
1
4
In fact, the model enyne used by Yu et al has not been tested experimentally. It does not display the
esters or the biphenyl group of 1 or 4. Thus, we decided to use the real gemꢀdiester tethered enyne 1
1
5
2
(E= CO Me) and the fluorene derivative 4 in the computations. With the latter (Table 3), both BS3
(Entry 1) and BS4 (Entry 2), which is the same as BS3 with the LANL2DZ+ECP basis set for In,
+
predict the correct isomer without invoking InCl
2
as active species. Moreover, with enyne 1, only the
(Entry 1) and M = InCl
formation of the nonꢀconjugated diene could be modeled with M = GaCl
Entry 2).
3
3
(
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Table 3. M06-2X Free Energies of Activation (kcal/mol) of the Key Step of the MCl
Catalyzed Cycloisomerization of Enynes 4 (left) and 1 (right)
3
-
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Entry Basis
TSa’-InCl3 TSb’-InCl3 TSa’’-GaCl3 TSb’’-GaCl3 TSa’’-InCl3 TSb’’-InCl3
[a]
set
[
b]
[c]
1
2
BS3
BS4
ꢀ
ꢀ
ꢀ
4.7 [6.9]
ꢀ
ꢀ
ꢀ
ꢀ
[b]
[c]
10.2
7.2
ꢀ
3.6 [6.2]
[a] BS3: 6ꢀ311+G(d,p) (all elements); BS4: 6ꢀ311+G(d,p) (C, H, O, Cl), LANL2DZ+ECP (In). [b] Not
found. [c] Free energy of activation of the unassisted 1,2ꢀHb shift.
Interestingly, the geometry of the most stable transition states leading to the nonꢀconjugated product
varies greatly when esters are present in the tether (Figure 1). Alkane and fluorene tethered systems
adopt a trans relationship between the migrating hydrogen and the cyclopentene framework (see TSb-
GaCl and TSb’-InCl ). On the other hand, a cis relationship is found in the gemꢀdiester tethered
3
3
transition states. The corresponding cis complexes have been computed as well and are significantly
less stable by ~ 2.5 kcal/mol (see values in brackets in Table 3). The stabilization observed in the cis
…
series is due to an interaction between the migrating hydrogen and one carbonyl oxygen. In O
H
area, inspection of the maximum electron density reveals quite strong hydrogen bonds (ρmax = 0.019
ꢀ3
ꢀ3
e.Å and ρ = 0.023 e.Å respectively for the Ga and In complexes). Thus, one ester group assists
max
the [1,2]ꢀH shift.
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Figure 1. Selected Geometries of the Most Stable 1,2-Hb Migration Transition States
Distances in Å)
(
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9
0
TSb-GaCl3
TSb’’-GaCl3
TSb’’-InCl
3
TSb’-InCl
3
Our calculations on the “real” fluorene and gemꢀdiester tethered systems show that there is no need
to coordinate the C=C bond of the cyclopentene moiety to favor the migration of Hb and obtain the
nonꢀconjugated product thereof. This rapid reꢀexamination of a previously studied reaction has
revealed that the choice of the level of theory is critical and that overꢀsimplifying the substrate in such
computations can lead to conclusions at odds with experimental results. It has also shown that the
presence of esters in the tether can favor specific conformations due to the presence of basic sites and
+
lower activation barriers. Since there is at present no reason to invoke MX
2
ions as active species in
MX ꢀcatalyzed transformations (M = Ga, In), GaCl
3
3
has been used in the next section.
3
2.2- GaCl -catalyzed Friedel-Crafts Reactions
1
6
It is wellꢀestablished that Group 13 salts are exquisite catalysts for FriedelꢀCrafts reactions.
Among them, gallium(III) halides are often more efficient and safer catalysts than the corresponding
1
7
aluminum salts. Although a few computational studies on Group 13 halideꢀcatalyzed FriedelꢀCrafts
1
8
reaction of simple compounds (benzene, acetyl chloride, 2ꢀchloropropane …) have been reported,
they reveal that the intimate mechanism is actually far more complex than anticipated. In particular,
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the deprotonation steps are not the same in AlCl ꢀcatalyzed FriedelꢀCrafts acylation and alkylation.
In both cases, the driving force to deprotonate the Wheland intermediate is the establishment of a
ꢀ
strong hydrogen bond with the chlorine bridged counterion Al Cl which plays the role of base.
2
7
ꢀ
However, for the alkylation, an Al
2 7
Cl ꢀassisted [1,2]ꢀH shift actually precedes the deprotonation. For
10
11
12
13
14
15
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Group 13 halideꢀcatalyzed hydroarylation of alkynes, alkenes, and allenes, theoretical studies are also
8
a,19
scarce and the deprotonation has not been studied.
the GaCl ꢀcatalyzed hydroarylation of 1,6ꢀarenynes and the subsequent bimolecular FriedelꢀCrafts
reaction of the resulting dihydronaphthalenes with anisole.
In this section, we investigate the mechanism of
3
It was previously reported that gemꢀdiester tethered arenynes such as 6 undergo GaCl ꢀcatalyzed
3
hydroarylation in 1,2ꢀdichloroethane (DCE) at 80 °C to give bicyclic compounds such as 7 (Scheme
3
a
4). When the reaction of 6 or 7 is carried out in DCE or toluene at 80 °C in the presence of an
aromatic nucleophile such as anisole, the adduct 8 is obtained.
Scheme 4. Ga(III)-Catalyzed Hydroarylation/Friedel Crafts Tandem of Arenyne 6
We have previously studied the hydroarylation mechanism by means of DFT computations at the
B3LYP/LANL2DZ+ECP(Ga),6ꢀ31G(d) (other elements) level, including solvent correction for
8
a
DCE. These results are summarized in Scheme 5. The coordination of the C≡C bond of 6 to give 9
triggers the nucleophilic attack of the benzene moiety to give 11 directly with a release of 43.6
kcal/mol of free energy. The transition state lies 13.6 kcal/mol above 9. The expected Wheland
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intermediate 10 did actually not converge. Dissociation of GaCl and thermodynamicallyꢀdriven
exocyclic/endocyclic shift of the C=C bond provides 7. The subsequent bimolecular FriedelꢀCrafts
step has not been studied computationally.
0
1
2
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8
9
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9
0
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0
1
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3
4
5
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8
9
0
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5
6
7
8
9
0
Scheme 5. Previously Reported Relative Free Energies (ꢀG298, kcal/mol) for the
8a
Hydroarylation of 6 at the B3LYP/BS1 Level (a Value over an Arrow Corresponds to the
Relative Free Energy of a Transition State)
We decided to reꢀinvestigate the hydroarylation mechanism and to study the FriedelꢀCrafts step at the
M06ꢀ2X/BS3 level (Scheme 6). To allow comparison with our previous results, solvent correction for
DCE was included.
Scheme 6. Free Energy Profile of the Hydroarylation of Arenyne 6 (ꢀG298, kcal/mol) at the
M06-2X/BS3 Level
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In the most stable isomer of 9, the two carbonyls adopt an anti relationship (Figure 2). Therefore, the
ortho hydrogens Ha and Hb of the benzene moiety are not equivalent and significant electron density
indicative of a nonꢀcovalent interaction was found between Hb and the nearby carbonyl oxygen
ꢀ
3
…
(O Hb 2.41 Å,
kcal/mol of free energy of activation and leads, as in the B3LYP case mentioned above, to 11 without
intermediate. This step is strongly exergonic by 46.0 kcal/mol. Migration of GaCl from the carbon to
ρmax = 0.011 e.Å ). The attack of the benzene carbon bearing Ha requires 17.7
3
one carbonyl oxygen results in a further release of 4.5 kcal/mol. If the Wheland intermediate had
converged, its transformation into 11 would have been the result of two suprafacial [1,2]ꢀH shifts
19
instead of a symmetry forbidden [1,3]ꢀH shift (Scheme 7). Inspection of the transition vector of TS9-
actually shows that it corresponds to the first [1,2]ꢀH shift. Yet neither 10 nor 10’ are stable and
11
collapse to 11 in the forward direction and to 9 in the backward direction.
Scheme 7. Resemblance Between TS9-11 and the Fictive TS10-10’
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9
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Cl Ga
Cl Ga
3
3
O
O
Cl Ga
3
Ha
Ha
[1,2]-shift
[1,2]-shift
O
O
Ha
O
O
O
O
9
O
O
O
O
10
10'
(not a stationary point)
11
(not a stationary point)
0
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9
0
1
2
3
4
5
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8
9
0
The attack of the carbon bearing Hb proceeds quite differently. It leads to the Wheland intermediate 13
which is formed in an exergonic fashion (ꢀG298 = ꢀ3.9 kcal/mol) through a transition state that lies
ꢀ3
…
only 6.5 kcal/mol above 9. In 13, the O Hb distance is only 2.09 Å and ρmax increases to 0.019 e.Å .
‡
Migration of Hb to O is achieved through a lowꢀlying transition state (ꢀG 298 = 5.6 kcal/mol for this
step) and 14 is formed in an appreciably exergonic fashion (ꢀG298 = ꢀ14.5 kcal/mol). The shift of Hb
from O to the carbon bearing the gallium atom is also straightforward as far as the free energy of
‡
activation is concerned (ꢀG 298 = 9.8 kcal/mol) and it is strongly exergonic (ꢀG298 = ꢀ27.6
20 21
kcal/mol). ,
Figure 2. Geometries of the Computed Species Shown in Scheme 6 (Distances in Å)
9
TS9-11
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1
12
TS9-13
13
TS13-14
14
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5
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5
6
TS14-11
The FriedelꢀCrafts reaction was studied next (Scheme 8 and Figure 3). Here again, we found two
pathways to reach compound 8 shown in Scheme 4 (i.e. 17 in Scheme 8 with GaCl coordinated to one
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
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9
0
1
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8
9
0
carbonyl oxygen of 8). The first one does not involve the esters (path 1). Complex 11 and anisole
‡
transform through a relatively lowꢀlying transition state (ꢀG 298 = 6.1 kcal/mol) into the Wheland
2
2
intermediate 15 in a virtually athermic fashion. A proton transfer giving rise to the σꢀcomplex 16 and
then the Oꢀcoordinated complex 17 was computed. Despite the downhill nature of this sequence
(
ꢀG298 = ꢀ12.6 kcal/mol to 16 and then ꢀ21.7 kcal/mol from 16 to 17), the [1,3]ꢀH shift requires a high
free energy of activation of 33.9 kcal/mol.
Scheme 8. Free Energies Profile of the Friedel-Crafts Step of the Tandem Transformation of
Arenyne 6 (ꢀ
G
298, kcal/mol) at the M06-2X/BS3 Level
TS15-16
-
11.4
path 1
TS20-17
-31.4
TS11-15 TS11-18
-39.9
-39.7
-46.1
path 2
-43.1
Cl3Ga
O
-46.0
Cl3Ga
Cl Ga
3
OMe
O
O
H
Ar
O
-55.8
Cl3Ga
-
58.0
O
O
-58.7
O
O
O
O
Cl Ga
3
GaCl3
O
O
H
11
+
O
Ar
O
H
Ar
O
O
15
H
20
O
O
H
O
Ar
OMe
O
O
O
-80.4
O
18
19
Cl Ga
O
3
O
Ar
1
6
O
O
Ar = p-OMe-C6H4
O
1
7
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Alternatively, 11 can react with anisole in a process which involves the simultaneous CꢀC bond
formation and cleavage of the CꢀH bond (path 2). One carbonyl oxygen of 11 serves as base to
E
deprotonate anisole which is found already aromatic in 18. Concerted S Ar mechanisms for arene
10
11
12
13
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16
17
18
19
20
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2
3
24
sulfonation and chlorination have been computed and refute the traditional textꢀbook perspective of
FriedelꢀCrafts reactions systematically involving Wheland σꢀcomplexes. However, the possibility of
concerted FriedelꢀCrafts alkylation involving a threeꢀcentered transition state is unknown to us
(Scheme 9).
Scheme 9. Possible concerted Friedel-Crafts alkylation
The free energy of activation of the concerted S
Isomers of 18 in which the proton is shared by the two carbonyl oxygen atoms (19) or is fixed at the
one cis to the GaCl fragment (20) were computed, yet they are less stable than 18. Nevertheless, from
0, oxygenꢀtoꢀcarbon migration can occur. The transition state of this protodemetallation step lies
E
Ar is virtually the same as the one to reach 15.
3
2
much lower in free energy than the one from 15 to 16 (ꢀ31.4 vs ꢀ11.4 kcal/mol). Therefore, the esterꢀ
assisted addition of anisole to 11 is the most favorable pathway.
Figure 3. Geometries of the Computed Species Shown in Scheme 8 (Distances in Å)
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TS11-15
15
TS15-16
16
17
TS11-18
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8
19
20
TS20-17
One could argue that the proton migration could take place in an intermolecular solventꢀmediated
8
a
fashion, yet the above reaction works equally well in toluene. Another possibility would be a
bimolecular process between two reaction intermediates; however, this scenario was ruled out by the
study of the reactivity of a substrate that does not display hydrogen bond acceptor functionalities: the
fluorene derivative 21 (Scheme 10). When submitted to GaCl in DCE or toluene, the hydroarylation
3
took place but not the FriedelꢀCrafts step.
Scheme 10. Ga(III)-Catalyzed Hydroarylation of Arenyne 21
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OMe
OMe
(
3 equiv)
Me
GaCl3 (10 mol%)
DCE or toluene
80 °C, 2 h
2
1
22
23 (unobserved)
0
1
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1
2
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8
9
0
Computations rationalize this feature (Scheme 11 and Figure 4). The hydroarylation proceeds in a
‡
25
concerted fashion through a lowꢀlying transition state (ꢀG
= 8.5 kcal/mol). The formation of 25 is
98
2
strongly exergonic (ꢀG298 = ꢀ48.6 kcal/mol). That of the Wheland intermediate 26 requires a modest
free energy of activation of 5.7 kcal/mol and is endergonic by 2.8 kcal/mol. Again, the
protodemetallation step (26 to 27 and then 28), although strongly exergonic (ꢀG298 = ꢀ9.2 kcal/mol and
then ꢀ25.2 kcal/mol) is compromised by a high activation barrier of 30.0 kcal/mol. Since there is no
basic sites in the substrates, there is no alternative route.
Scheme 11. Free Energy Profile of the Hydroarylation/Friedel-Crafts Transformation of
Arenyne 21 (ꢀG298, kcal/mol) at the M06-2X/BS3 Level
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TS24-25
8
.5
0
.0
GaCl3
TS26-27
-
15.8
10
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24
+
OMe
TS25-26
-
42.9
-
45.8
-
48.6
Cl Ga
3
OMe
Cl Ga
H
3
-55.0
GaCl
3
H
OMe
2
6
2
5
+
Cl
3
Ga
OMe
OMe
-80.2
27
28
Figure 4. Geometries of the Computed Species Shown in Scheme 11 (Distances in Å)
24
TS24-25
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5
TS25-26
26
TS26-27
27
28
Even though the calculations presented in Sections 2.1 and 2.2 are restricted to Group 13 metalꢀ
catalyzed reactions involving gemꢀdiester tethered substrates, there is no reason to believe that the
conclusions reached would not apply to other kind of transformation involving a proton transfer, as
long as a functional group such as an ester is well enough located to shuttle the migrating hydrogen.
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To address this issue, we have next studied a platinum(II)ꢀcatalyzed reaction in which the substrate
does not display a gemꢀdiester tether, but a simple ester substituent at the reacting alkyne unit of an
arenyne.
10
11
12
13
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2
.3- PtCl
2
-Catalyzed Hydroarylation of 1,6-Arenynes
In this section, we turn our attention to the hydroarylation of biphenylacetylenes described by
2
6
Fürstner for the following reasons: i) not only main group metal salts but also transition metal
complexes such as PtCl are known to be active catalysts for this transformation; ii) the cyclization of
a substrate displaying a single ester group has been carried out; iii) the mechanism has already been
2
1
9
studied by Soriano but the possibility of esterꢀassisted proton transfer has not been considered. In
fact, the cyclization of such substrates can lead to fluorenes or phenanthrenes, the latter type being the
major one when PtCl
2
is used as catalyst, except with an ester at the alkyne terminus as in 29 (Scheme
1
2). In this case, the fluorene derivative 30 is formed selectively as an E/Z mixture.
Scheme 12. Platinum-Catalyzed Cycloisomerization of Compound 29
From B3LYP/LANL2DZ+ECP(Pt),6ꢀ31G(d) (other elements) computations using on a simplified
model substrate, Soriano and MarcoꢀContelles proposed a mechanism involving a 5ꢀexoꢀdig or a 6ꢀ
endo-dig attack of the arene onto the complexed C≡C bond, followed by two [1,2]ꢀH shifts. They
showed that the reversal of selectivity between the 5ꢀexo and the 6ꢀendo pathways was due to the
polarization of the C≡C bond induced by the ester. The preference for the 5ꢀexoꢀdig cyclization was
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6
shown on the “real” substrate 29, but the [1,2]ꢀH shifts were not computed in this case. Intrigued by
the proximity of the carbonyl group with the migrating proton in complex 33, we decided to compare
the [1,2]ꢀH shifts sequence with an esterꢀassisted proton transfer (Scheme 13 and Figure 5). From our
part, we used the B3LYP/LANL2DZ+ECP(Pt),6ꢀ311+G(d,p) (other elements) level for the geometry
optimizations and to get the thermal corrections to the free energies. We then carried out single point
calculations using the M06 functional, the SDD basis set for Pt, and the 6ꢀ311+G(d,p) basis set for
other elements. A barrier of 18.2 kcal/mol was computed for the transformation of starting complex 32
into the Wheland intermediate 33, which represents the rate determining step. From 33, 13.3 kcal/mol
of activation energy are required to give the platinum carbenoid 34. The second [1,2]ꢀH shift leading
to the complexed alkene 35 is achieved at a free energy cost of 23.9 kcal/mol. The entire sequence is
downhill with a total exergonicity of 25.3 kcal/mol. From 33, the capture of the proton proceeds
straightforwardly through a 7.4 kcal/mol activation barrier. A virtually barrierless rotation of the
0
1
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9
0
…
protonated ester in 36 yields 37, which is greatly stabilized by an OH Cl hydrogen bond.
Protodemetallation finally takes place through a 20.4 kcal/mol activation barrier to give 38, which is
actually the diastereomer of 35. Indeed, the migration of the proton to the metallated carbon atom
requires rotation of the C=C bond. The overall 33→38 process is also downhill and is kinetically
favored over the 33→35 pathway.
Scheme 13. Free Energy Profile of the Hydroarylation of Arenyne 32 (ꢀ
M06 Level
G298, kcal/mol) at the
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TS32-33
TS33-34
18.2
1
1.2
TS33-36
TS34-35
.9
TS37-38
5.3
2
0
.0
-0.6
-
2.1
TS36-37
OMe
O
OMe
O
Cl Pt
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12
13
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32
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Cl Pt
2
-11.6
2
-11.7
OMe
H
Cl Pt
2
H
-21.0
-19.8
Cl
OH
H
OMe
O
-25.3
33
Cl Pt
O
-26.8
32
2
Pt
OMe
O
O
H
Cl
OMe
H
3
6
Cl Pt
2
MeO
Cl Pt
H
2
34
37
35
3
8
Figure 5. Geometries of the Computed Species Shown in Scheme 13 (Distances in Å)
3
2
TS32-33
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33
TS33-34
34
TS34-35
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TS33-36
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TS36-37
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TS37-38
38
Thus, the ester group at the alkyne enables a mechanistic alternative. It can serve as proton carrier to
ensure the rearomatization of the Wheland intermediate and the protodemetallation step.
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3- Conclusion
The above computations indicate that the ester functionality can play an active chemical role in metalꢀ
catalyzed carbocyclization and FriedelꢀCrafts reactions by shuttling protons from one place to another.
E
In particular, a rare kind of concerted S Ar where the ester functionality acts as base has been
0
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uncovered. While the ability of carbonyls to transfer hydrogens is wellꢀknown in the coordination
sphere of a metal (for instance inner sphere pivalateꢀassisted concerted metalation deprotonation
2
7
(
CMD)), it is overlooked in metalꢀcatalyzed reactions occurring under substrate control.
4- Experimental Section
2
8
Computations. All the calculations were performed using the GAUSSIAN 09 software package.
For the study of galliumꢀ and indiumꢀcatalyzed reactions, the structures were optimized and
characterized to be energy minima (no imaginary frequency) or transition states (one imaginary
2
9
30
frequency) at the M06ꢀ2X level. The 6ꢀ311+G(d,p) basis set (BS3) was used for C, H, N, Cl, O, and
3
1
Ga, and the LANL2DZ+ECP basis set was used for In (BS4). The thermal corrections to free
energies were carried out at 298.15 K and 1 atm using the M06ꢀ2X harmonic frequencies (ꢀG298).
Solvent corrections to the free energies were obtained for 1,2ꢀdichloroethane (DCE) with the CPCM
3
2
model. For the study of the platinumꢀcatalyzed reaction, computations were carried out at the
3
3
31
30
B3LYP level using the LANL2DZ+ECP basis set for Pt and the 6ꢀ311+G(d,p) basis set for the
other elements. Single point calculations using the B3LYP optimized geometries were carried out with
29
34
the M06 functional and a larger basis set of SDD for Pt. The thermal corrections to free energies
were obtained at 298.15 K and 1 atm using the B3LYP harmonic frequencies (ꢀG ).
2
98
General Information. All reactions were performed in ovenꢀdried flasks under argon atmosphere.
Unless otherwise stated, commercially available reagents were used as received without further
purification. Gallium, and indium halides were obtained from Alfa Aesar and used as received. Silver
hexafluoroantimonate was purchased from SigmaꢀAldrich and used as received. 1,2ꢀDichloroethane
was distilled from calcium hydride and degassed by FreezeꢀPumpꢀThaw technique. Unless otherwise
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stated, products were purified by chromatography over silica gel. TLC plates were visualized by UV
light (254 nm) and pꢀanisaldehyde staining. GC analysis was performed with a nonꢀpolar column (15
m x 0.25 mm x 0.25 mm) NMR spectra were recorded on 360 and 300 MHz spectrometers. Chemical
1
13
shifts are reported in parts per million (ppm). The spectra were referenced to the residual H and C
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1
13
signals of the solvents as follows: CDCl
following order: chemical shift, multiplicity (s = singlet, d = doublet, m = multiplet), coupling constant
J) in Hz and integration. Infrared spectra were recorded on a FTIR spectrometer (KBr pellets) and are
3
( H, δ = 7.27 ppm; C, δ = 77.0 ppm). Data are given in the
(
ꢀ1
reported in cm . HRMS were performed by electrospray ionization using a qTOF mass spectrometer.
35
36
11
IPr·GaCl
3
,
IPr·InBr3, and [Ag][Al(pftb)
4
] were prepared following reported procedures. Enyne 1
4a
was synthesized according to a previously described method. Arenyne 6 was prepared following a
8a,8b
reported procedure.
The synthesis and characterization of compounds 7 and 8 were previously
8
a
8b
reported by our team. Arenyne 21 and cycloalkene 22 were also described previously.
Procedures for the Cycloisomerization of Enyne 1
General considerations: the substantial difference between conversions and isolated yields can be
2
explained by polymerization occurring as side reactions. Thus, rinsing silica gel with Et O after flash
chromatography leads to the recovery of the missing material as a very complex mixture. These
1
complex mixtures were already observed by HꢀNMR analysis of the crude product before the
4
a
purification step. Also, as Yu et coll. have previously stated, the generated dienes are stable on silica
gel. Moreover, no other isomers arising from 1 could be observed by GC monitoring. The NMR
spectra of 2 displayed in the Supporting Information were obtained from condition B as a
representative outcome of a mainꢀgroup metalꢀcatalyzed cycloisomerization of 1.
3
Condition A: IPr·GaCl (5 mol%, 0.0125 mmol, 7.06 mg) was dissolved in DCE (0.5 mL) in a
screwꢀcap vial under argon. [Ag][Al(pftb) ] (7 mol%, 0.0175 mmol, 18.81 mg) was added and the
4
mixture was stirred for 5 min. A solution of enyne 1 (0.25 mmol, 59.6 mg) in DCE (0.5 mL) was
added and the reaction mixture was stirred at 80 °C for 4 h. After filtration over a short pad of Celite
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