Gold(I) Catalysis
Taschinski, Svenja
DOI:
10.33612/diss.126022756
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2020
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Taschinski, S. (2020). Gold(I) Catalysis: Mechanistic Insights, Reactivity of Intermediates and its
Applications. University of Groningen. https://doi.org/10.33612/diss.126022756
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Chapter 2
Mechanistic Investigation of the
Divergence of a Light-Mediated
Gold-Catalyzed Reaction
Abstract: In this chapter, the conditions for a gold-catalyzed light-mediated reaction are
explored. o-Alkynylphenols and diazonium salts can be converted into substituted benzofurans upon irradiation with blue LED under N2-extrusion or into substituted azobenzofurans with N2-retention in the absence of light. With essentially the same reaction conditions, starting materials react selectively either under C-C-bond formation or C-N-bond formation, respectively.
Furthermore, the mechanistic pathways are investigated by isolation of a vinyl gold(I) complex and conduction of stoichiometric experiments, which implicate this complex as a common intermediate in both pathways.
In contrast to previous reports in literature, arylative coupling is realized without the addition of a photo(redox) catalyst under ambient conditions. To explore how the photochemical activation is feasible, DFT calculations were performed proposing an Electron-Donor-Acceptor-Complex as a key intermediate, formed by a vinyl gold(I) complex and a diazonium salt.
Parts of the results are published in: Angew. Chem. Int. Ed. 2019, 58, 16988-16993; Angew. Chem. 2019, 131, 17144-17149; "Light-Induced Mechanistic Divergence in Gold(I) Catalysis: Revisiting the Reactivity of Diazonium Salts"
30
2.1)
Introduction
Photochemical transformations involving redox processes for C-C-bond formation have been demonstrated in various reactions.[1] Among the well-known photoreactions using transition metals, such as Ir, Ru, Rh for single-electron transfers (SETs),[1] many advantages have been realized in the use of dual-gold photoredox and gold-only (photoredox) catalysis for C-C-bond formation,[2] in which diazonium salts are used as aryldonors for coupling-reactions.[3] Arylative coupling has been explored for different types of substrates, for example in cross-coupling reactions with allenoates by homolytical cleavage of the C-N-bond to provide radicals using thermal N2-extrusion (see Scheme 12).[3x]
Scheme 12: Gold-catalyzed arylative coupling under thermal conditions by Shin and co-workers.[3x]
Besides the thermal generation of the radical, a photochemical gold-only mechanism is reported via SETs through the oxidative addition of the diazonium salt to the gold-precursor, forming a gold(III) complex without an additional photo catalyst.[3j, 3v, 3w] Our group demonstrated a gold-catalyzed arylation to generate -aryl ketones 36 by light-mediated C-C-bond formation featuring diazonium salts (see Scheme 13).[3v, 3w] The catalytic cycle is proposed to start with an initial SET from gold(I) to the diazonium salt forming a gold(II) intermediate and an aryl diazo radical that both recombine to a gold(III) intermediate. Once the gold(III) species is formed (the formation might also be possible by direct addition of the diazonium salt to the gold(I) pre-catalyst), a light-mediated N2-extrusion forms the active gold(III) species that coordinates to and activates the multiple bond. Subsequent back-side attack of the intermolecular nucleophile to the multiple bond and reductive elimination terminates the catalytic cycle under product formation 36 and recycles the pre-catalyst.[3v, 3w]
Scheme 13: Gold-catalyzed arylative coupling under photo catalyst-free conditions by Hashmi and co-workers.[3v, 3w]
At the same time, Fensterbank and co-workers reported a dual photoredox gold-catalyzed approach for the synthesis of substituted benzofurans 37 using diazonium salts under blue LED irradiation (see Scheme 14).[3s] The oxidative arylation of the gold(I) pre-catalyst to the catalytically active gold(III) species is featured by two SETs from the co-catalyst [Ru(bpy)3](PF6)2.
31
Introduction
Scheme 14: Dual gold-catalyzed photo(redox) catalysis to substituted benzofurans by Fensterbank and co-wokers.[3s]
The mechanism of the arylative coupling proposed by Fensterbank and co-workers[3s] involves a second catalytic cycle. The additional photo catalyst ([Ru(bpy)3](PF6)2) generates a phenyl radical E by light-mediated SET which is reacting with the gold(I) precursor 38 and gold(II) species F is formed (see Scheme 15). By a second SET, the same photo catalyst is proposed to oxidize F to the gold(III) species G, which is afterwards coordinating to the triple bond, facilitating an intramolecular nucleophilic attack and vinyl gold(III) intermediate I is formed. Deprotonation by base and reductive elimination to product 37 closes the catalytic cycle.
Scheme 15: Proposed reaction mechanism for the dual-photo(redox) catalytic arylation involving diazonium salts by Fensterbank and co-workers.[3s]
32
This type of reactivity has already been reported in several other studies[3b, 3f, 3ad, 4] and stoichiometric reactions for the oxidative addition of diazonium salts to gold complexes support the proposed mechanistic pathway through a gold(III) intermediate.[3v, 3w, 5]
A few years earlier, a reaction was reported by our group[6] using o-alkynylphenol 25
OMe and
diazonium salt 34OMe to form a C-N-bond with N2-retention of the diazonium salt. The reaction to substituted azobenzofuran 32OMe,OMe does not involve a change in oxidation state, but
instead a mechanism that proceeds through a vinyl gold(I) intermediate 46OMe,IPr which is
trapped electrophilically by the diazonium salt 34OMe (see Scheme 16).[6b]
Scheme 16: Stoichiometric experiments for the formation of azobenzofuran 32OMe,OMe.[6b]
Although first attempts have been successful in optimizing the reaction conditions, a very limited number of substrates were isolated in moderate to high yields when using two different catalysts and diazonium salts.[6]
Scheme 17: Isolated azobenzofurans 32 reported by Döpp.[6a]
Inspired by the work of Fensterbank and co-workers,[3s] who used diazonium salts for arylative C-C-bond formation (see Scheme 14) and previous work in our group[6] which made use of essentially the same starting materials to form C-N-bonds (see Scheme 16 and Scheme 17), the aim of this project was to explore if both reactions may have a common vinyl gold intermediate, such as other gold-catalyzed transformations previously reported,[4, 7] and where the difference in reactivity originates.
33
Introduction
Both reactions start with a substituted o-alkynylphenol 25 that reacts in the presence of a gold catalyst with diazonium salt 34 either to substituted benzofurans 37 or azobenzofurans 32 (see Scheme 18). The varied reaction conditions are proposed to lead to different intermediates in the reaction mechanisms, a vinyl gold(III) and a vinyl gold(I) intermediate, respectively (vide supra).
Scheme 18: Similarities and differences of the reaction reported by Fensterbank and co-workers (top) and our goup (bottom).[3s, 6]
In the following chapter, the reaction conditions for a divergent gold-only catalysis using the same starting materials are explored to form C-C- and C-N-bonds, respectively. A mechanistic study considering a vinyl gold(I) intermediate is demonstrated and supported by DFT calculations. Both reactions are briefly optimized and probed to a limited extent in regard to scope.
34
2.2)
Results and Discussion
In the following section, mechanistic studies and catalytic experiments are described. The similarities and differences in reactivity are explored using the same starting materials under the same reaction conditions to form substituted arylated benzofurans 37 and azobenzofurans 32, respectively.
Scheme 19: Divergence in Au-catalyzed reactions leading to formation of arylated benzofurans 37 (N2-extrusion) without additional photo(redox) catalyst and substituted azobenzofurans 32
(N2-retention).
To probe whether or not there are similarities and differences in reactivity, the same starting materials were treated in the presence or absence of light with different catalysts varying the solvent, base and counter anion of the gold-catalyst (see Table 1). All experiments were carried out without an additional photo(redox) catalyst. The arylation of o-alkynylphenol 25Me
with diazonium salt 34H using a blue LED light source was feasible with catalytic amounts of
Ph3PAuCl in the absence of an additional photo catalyst providing the desired product 37Me,H
in 46% yield (entry 1) and small amounts of azobenzofuran 32Me,H were formed in the absence
of light using MeCN and CH2Cl2, respectively. Changing the anion of the gold complex to the weakly coordinating NTf2- increased the yield of azobenzofuran 32Me,H as expected, but
surprisingly increased the yield of arylated benzofuran 37Me,H as well (entry 2). In an effort to
avoid protodeauration more efficient, the more soluble base 2,6-ditertbutylpyridine (DTBP) was used, however, it did not have a beneficial effect under these reaction conditions (entries 3 and 4).
These experiments clearly demonstrate that the reaction mechanism can be controlled using the same starting materials under the same reaction conditions by simply irradiating with light.
35
Results and Discussion
Table 1: Comparison of reactions conditions used to show the mechanistic divergence.
Entry Catalyst Base Yield 37Me,H [%] irradiation at 450 nm[a,c] Yield 32Me,H [%] No irradiation[a,b] MeCN CH2Cl2 MeCN 1 Ph3PAuCl NaHCO3 46[d,e] 5 7 2 Ph3PAuNTf2 NaHCO3 54[d,e] 22[d] 11 3 Ph3PAuCl DTBP
4 not observed not observed
4 Ph3PAuNTf2
DTBP
11 19 23
[a] Averages of duplicate runs are given. [b] General conditions: 25Me (50 µmol), [Au] (5.00 mol-%), 34H (100 µmol), base (100 µmol), solvent (500 µL), r.t., 24 h, determined using 1H NMR spectroscopy with benzyl acetate as internal standard. [c] General conditions:
25Me (100 µmol), [Au] (5.00 mol-%), 34H (200 µmol), base (200 µmol), solvent (1 mL), r.t.,
2 h, 450 nm light source, determined using GC MS with hexamethylbenzene as internal standard. [d] Full conversion of starting material. [e] With Au and a ruthenium photo(redox) catalyst present, similar yields were obtained with related substrates, see Ref. [3s].
Control experiments demonstrate the necessity of the gold catalyst for both cases and the results are shown in section 2.2.1). Stoichiometric experiments were performed to explore the involvement of a gold(I) intermediate and irradiation of the (pre-)catalyst in the presence of diazonium salt indicates, that the previous oxidation of the gold(I) precursor to a gold(III) species in the present case is not feasible (see paragraph 2.2.2), 2.2.3) and 6.2.5). DFT calculations support the hypothesis of an Electron-Donor-Acceptor-Complex, that is formed during the reaction between gold(I) complex and the diazonium salt as shown in paragraph 2.2.4). Further irradiation experiments demonstrate that the arylated product is consumed by the diazonium salt under irradiation explaining the moderate yields (see 2.2.5). The scope for both reactions is briefly probed as shown in section 2.2.5) and 2.2.6).
36
2.2.1) Control Experiments
To probe that the arylative coupling of o-alkynylphenols 25 and diazonium salts 34 to substituted benzofurans 37 is gold-catalyzed and light-mediated, several control experiments were conducted which are shown in Table 2. Further irradiation experiments have been accomplished to proof if the essential formation of a gold(III) intermediate prior to the activation of the triple bond of the substrate is possible. Moreover, a possible consumption of the arylated product 37Me,H was tested by treatment with an excess of diazonium salt. Additional control
experiments for the gold-catalyzed formation of azobenzofurans 37Me,H were carried out and
the results are shown in Table 3.
2.2.1.1) Arylated Benzofurans
As shown in Table 2, arylative coupling is observed in the absence of the gold catalyst by adding diazonium salt only (entry 1). The product was formed in trace amounts by adding base under the same reaction conditions (< 5%, entry 2). The possible formation of benzofuran 41Me as an intermediate was tested by exposure to diazonium salt only and small
amounts of product were observed (entry 3). Basic reaction conditions (entry 4) and additionally added Ph3PAuNTf2 yielded low amounts of arylated benzofuran 37Me,H. Neither
AgNTf2 (entry 7), nor HBF4 (entry 6) catalyzed the reaction efficiently but yielded traces of product.
The irradiation of solely azobenzofuran 32Me,H as well as 32Me,H under
reaction conditions did not lead to the loss of nitrogen demonstrating that azobenzofurans can not be converted into substituted benzofurans 37Me,H (entries 8 and 9, see Figure 2).
Figure 2: Azobenzofuran 32Me,H solely in MeCN (left) and azobenzofuran 32Me,H under reaction
conditions (right) after irradiation with blue LED. Table 2: Control experiments for the formation of arylated benzofurans.
Entry Starting
Material Catalyst Base
Yield 37Me,H [%] Irradiation 1 TS-696 25Me No No Not observed 2 TS-647 25Me No NaHCO3 < 5 3 TS-698 41Me No No 5 4 TS-679-B 41Me No NaHCO3 17
5 TS-679-A 41Me Ph3PAuNTf2 NaHCO3 15
6 TS-696 25Me HBF4(a) No < 5
7 TS-692 25Me AgNTf2(b) NaHCO3 < 5
8 TS-701-A 32Me,H(c) No No Not observed
9 TS-701-B 32Me,H(d) Ph3PAuNTf2 NaHCO3 Not observed
(a) 7.7 mol-% HBF4. (b) 6.2 mol-% AgNTf2. (c) 30 µmol in 200 µL MeCN. (d) 50 µmol in 500 µL MeCN,
37
Results and Discussion
2.2.1.2) Azo compounds
The formation of azobenzofuran 32Me,H was not observed under the conditions shown in Table 3. Neither treatment of the starting material with the diazonium salt, nor adding additional base
yielded the desired product (entries 1 and 2). Product formation was not observed when treating benzofuran 41Me with diazonium salt solely or with catalyst under reaction conditions
(entries 3 and 4). AgNTf2 (entry 6) and HBF4 (entry 5) did not function as a catalyst.
Table 3: Control experiments for the formation of azobenzofuran 32Me,H.
Entry Starting
Material Catalyst Base
Yield 32Me,H [%]
No irradiation
1 TS-695 25Me No No Not observed
2 TS-663-KE 25Me No DTBP Not observed(a)
3 TS-678-C 41Me No DTBP Not observed
4 TS-678 41Me Ph3PAuNTf2 DTBP Not observed
5 TS-690 25Me HBF4(b,c) No Not observed
6 TS-689 25Me AgNTf2(b,d) DTBP Not observed
(a) Different substituted azo compound observed (see Scheme 20 and 6.2.4.3), (b) 4 eq of 34H. (c)15.3 mol-% HBF4. (d)6.7 mol-% AgNTf2.
A differently substituted azo compound 42 was formed under basic conditions in low yields after 19 days (entry 2, see Scheme 20 and 6.2.4.3). Without catalyst, the starting material 25Me is deprotonated prior to the reaction with the diazonium salt forming the quinoic
species K / L. The electron-rich diazonium salt 34Me reacts under electrophilic addition to the
deprotonated species K / L and forms the side product 42. The side product 42 can also be observed in traces with electron-poor diazonium salts under gold-catalyzed conditions.
38
Scheme 20: Variously substituted azo compound 42 observed under basic conditions (see 6.2.4.3).
The THP-protected alkynol 45 was synthesized in high yield and treated with diazonium salt 34Me (see Scheme 21) to investigate, if a protecting group might affect the gold-catalyzed
formation of azobenzofurans. The THP-group is cleaved during the reaction, but the formation of the Au complex seems to be slower due to the protecting group at the oxygen atom explaining the low yield of the desired product 32H,Me.
Scheme 21: Synthesis of THP-protected alkyne 45 and its formation under reaction conditions to azo compound 32H,Me.
The relevance of this experiment will be further explored later in Chapter 4 by investigation of the formation of (bisazo)benzo[b,b’]difurans.
39
Results and Discussion 2.2.2) Irradiation Experiments
The possibility that oxidative addition of the diazonium salt to the gold(I) (pre-)catalyst occurs first was evaluated through the treatment of insoluble Ph3PAuCl and soluble Ph3PAuNTf2 with diazonium salt 34Me. Irradiation of the mixture with blue LED for more than two hours did not
alter the concentrations of the substrates in solution (i.e. over the same time during which the catalytic reactions were performed in Table 1; monitored with 1H NMR spectroscopy).
Figure 3: Mixtures monitored by 1H NMR spectroscopy in CD
3CN while under irradiaton at 405 nm
(see 6.2.5). The pictures in the middle show the NMR tubes before irradiation.
Based on the irradiation experiments performed, oxidation of the gold(I) catalyst which might occur before coordinating to the triple bond of the alkyne in substrate 25can be excluded. However, activation of the gold(I) catalyst with a change in oxidation state after the coordination to the triple bond can not be ruled out.
40
2.2.3) Stoichiometric Experiments
Considering the earlier observations shown in Table 1 and previous work by our group,[6] the vinyl gold(I) complex 46Me,Ph3P was isolated (see Scheme 22)[7d] with the aim to probe if the
reactions shown in Scheme 19 involve a common intermediate.
Scheme 22: Isolation of vinyl gold(I) complex 46Me,Ph3P according to a modified procedure by
Hashmi and co-workers,[7d] and solid state X-ray structure of vinyl gold(I) complex 46
Me,Ph3P. Thermal ellipsoids are shown at 50% probability, hydrogen atoms are omitted for clarity.
The air-stable complex 46Me,Ph3P could be isolated in high yield and was treated with diazonium
salt 34H with and without irradiation (see Scheme 23).
Azobenzofuran 32Me,H was formed in 46% yield without irradiation (determined by 1H NMR
spectroscopy, full conversion of starting material) and confirms the previous result determined by Ackermann,[6b] who treated 46
OMe,IPr with 2.00 eq 34OMe and isolated
azobenzofuran 32OMe,OMe with 42% yield (see Scheme 16). Irradiating a similar sample with
blue LED yielded 65% of arylated benzofuran 37Me,H under N2-extrusion (determined by GC MS, full conversion of starting material). A similar experiment, reported earlier by Shin and co-workers was conducted by treating an isolated vinyl gold(I) intermediate with a diazonium salt to achieve C-C-bond formation but still required the presence of a photo catalyst ([Ru(bpy)3](PF6)2).[3x]
Next to the consumption of the arylated species, which was explored in 2.2.2), a major side product observed for both reactions is benzofuran 41Me which is attributed to the
protodeauration of vinyl gold(I) complex 46Me,Ph3P. In a stoichiometric experiment, the
formation of 41Me was confirmed by treating vinyl gold(I) complex 46Me,Ph3P with phenol as a
proton source. In both reaction types with catalytic amount of the gold catalyst (see Table 1 and 2.2), a large excess of starting material 25Me is present which is identified as a possible
41
Results and Discussion
Scheme 23: Reactivity of the isolated vinyl gold(I) complex 46Me,Ph3P towards diazonium salt 34H
with and without irradiation and towards phenol and starting material 25Me.
The stoichiometric reactions shown in Scheme 23 indicate that both reactions proceed through a similar reaction mechanism, where a vinyl gold(I) intermediate is formed. The experiments conducted demonstrate that in case of an oxidative addition of the diazonium salt, the gold(III) intermediate is not formed before the coordination to the triple bond but might occur after the formation of vinyl gold(I) intermediate 46R,L. Therefore, a possible mechanism
for both reactions is outlined in Scheme 24. In both cases, the Lewis-acidic gold(I) complex coordinates to the alkyne, increases electrophilicity of the triple bond and facilitates an intramolecular nucleophilic attack of the phenolic oxygen to form the vinyl gold(I) intermediate OR,L under 5-endo-dig cyclization. Deprotonation by base provides
complex 46R,L that can be isolated and electrophilically trapped by the diazonium salt without
irradiation with N2-retention to from azobenzofuran 32. Alternatively, the photolytically cleaved diazonium salt acts as a C-electrophile to deaurate complex 46R,L to arylated benzofuran 37
42
43
Results and Discussion 2.2.4) DFT Calculations
With the results of the stoichiometric experiments shown in 2.2.3), the question arose how photochemical activation is possible with colorless starting materials which do not show absorption bands in their UV-VIS spectra at irradiation wavelength 450 nm and 405 nm (see
Figure 4).
Figure 4: UV-VIS absorption spectra of 46Me,Ph3P (49.4 µM in CH2Cl2) and 34H (52.1 µM in MeCN).
DFT calculations[8] support the formation of an Electron-Donor-Acceptor-Complex (EDAC) for the arylative coupling, which is formed during the reaction of vinyl gold(I) complex 46Me,Ph3P
and the diazonium salt 34H. Geometry optimizations for the singlet state I and the triplet state II
44
Figure 5: Electron-Donor-Acceptor-Complex formed between 46Me,Ph3P and 34H; structural
depictions of fully optimized geometries of donor-acceptor complexes I and II at the TPSS-D3(BJ)/def2-SVP/PCM(MeCN) level of theory (right).
The experimental and computed spectra of both starting compounds indicate[8] that neither the complex 46Me,Ph3P, nor the diazonium salt 34H can be photolytically activated upon
irradiation with visible light and calculations confirm their lowest lying excited states at 319 nm and 293 nm, respectively. For the proposed EDAC I several excited states at lower energy can be found (429, 383, 377, 343 and 320 nm), supporting the involvement in photochemical activation due to charge transfer effects (see Figure 6).
Figure 6: Calculated UV-VIS spectrum of Electron-Donor-Acceptor-Complex I.
Calculations demonstrate, that the proposed EDAC I has its HOMO located at the vinyl gold(I) core and LUMO located at the coordinated diazonium salt (see Figure 7), where a low-lying excited state at 624 nm corresponds to HOMO-LUMO charge-transfer.
45
Results and Discussion
Figure 7: HOMO and LUMO depictions of the donor-acceptor complex I at the CAM-B3LYP-D3(BJ)/def2-SVPD/PCM(MeCN)//TPSS-D3(BJ)/def2-SVP/PCM(MeCN) level of theory.
The identified low-lying excited state allows for the energy profile of the reaction to be mapped. An energy increase of 45.8 kcal mol-1 for the excited state I above the ground state S
0 of the EDAC can be found for the singlet state. The triplet state II is calculated with an energy level of 29.17 kcal mol-1 which is lowered to 13.2 kcal mol-1 at the fully relaxed triplet geometry (see
Figure 8).
Figure 8: Energy profile for relevant species for the photochemical activation via the
donor-acceptor-complex I at the (TD-)CAM-B3LYP-D3(BJ)/def2-SVPD/PCM(MeCN)//TPSS-D3(BJ)/def2-SVP/PCM(MeCN) level of theory.
Regarding the results, the photochemical activation might proceed through an initial excitation from the ground state S0 of EDAC I to S1, which relaxes with intersystem crossing to its energetically favored triplet state T1 and finally undergoes geometric relaxation to its triplet state II. A possible pathway might also be the excitation to a higher excited state where previous internal conversion leads to the low-lying excited state S1, a scenario that can not be excluded based on the calculations available. During the process on the triplet surface, the length of the C-N-bond at the diazonium salt fragment increases from 1.362 Å to 1.449 Å which indicates that the following C-C-bond formation takes place on the triplet surface.
46
2.2.5) Substrate Scope Substituted Benzofurans
The scope of the reaction was probed after optimizing the reaction conditions as shown in
Table 1. Arylative coupling can be reached using various diazonium salts with
electron-donating and -withdrawing effect in moderate yields, respectively (see Scheme 25).
Scheme 25: Substrate scope for the formation of substituted benzofurans 37.
The substitution pattern at the diazonium salt has a minor effect on the yield with full conversion of the starting material 25Me, giving moderate yields for electron-donating
and -withdrawing groups, respectively. The reaction proceeds faster if the diazonium salts contain an electron-withdrawing group with positive mesomeric effect, such as the NO2-group, which is demonstrated by decreasing the reaction time to 30 minutes with a detrimental effect on yield. These data indicate a reaction rate that is dependent on the electronic nature of the diazonium salt. This effect is observed the other way around when 25Me is treated with 34Me,
where the reaction time is increased to four hours (see Scheme 25). In contrast to the previous report of Fensterbank and co-workers[3q] the electron-withdrawing NO
2-group at the diazonium salt formed 37Me,NO2 in low yield with full conversion of starting material 25Me. This trend can
be observed also when changing the substitution pattern at the alkyne from the electron-donating Me- to the electron-withdrawing F-group, giving 42% yield with the NO2-substituted diazonium salt 34NO2. When changing to the non-substituted diazonium salt 34H, the starting
material 25F could not be fully converted into the desired product even when extending the
reaction time up to 16 hours and increasing the amount of diazonium salt up to four equivalents.
47
Results and Discussion
These results demonstrate that the reaction conditions and the substitution pattern of the alkyne have a crucial role on the reactivity of the system.
To explore why the reaction proceeds with such low yields, irradiation experiments of 37Me,NO2
in presence of diazonium salt 34NO2 were performed which show that the formed
benzofuran 37Me,NO2 is consumed under reaction conditions (see Figure 9).
Figure 9: 1H NMR spectra (399.82 MHz, CD
3CN) of starting materials before and after irradiation
48
2.2.6) Substrate Scope Substituted Azobenzofurans
Based on previous reports by Ackermann[6b] and Döpp[6a] and the comparison reactions shown in 2.2) Table 1, the reaction conditions for the formation of azobenzofuran 32Me,H were briefly
optimized. The average yields in Table 4 were determined by 1H NMR spectroscopy after 24 hours reaction time in duplo.
Table 4: Optimization reactions for the formation of azobenzofuran 32Me,H.
Entry Catalyst Base Yield 32Me,H [%] No irradiation Solvent CH2Cl2 MeCN 1 IMesAuNTf2 2.00 eq NaHCO3 10(a) 22 2 IMesAuNTf2 2.00 eq DTBP 68 17 3 IMesAuNTf2 1.20 eq DTBP 63 (b) - 4 IMesAuNTf2 1.20 eq DTBP 64(c) 67(d) -
(a) Full conversion of starting material. (b) Full conversion of starting material after 48 hours. (c) Single run, 150 µmol (3.00 eq.) 34H was used. (d) Single run, 200 µmol (4.00 eq.) 34H was used.
Confirming the results shown before, the insoluble base NaHCO3 did not lead to a higher amount of product, neither with Ph3PAu-complexes, nor changing to a catalyst with the IMes-ligand (entry 1). The use of DTBP as a more soluble base increased the yield of azobenzofuran 32Me,H from 19% using the Ph3P-ligand (Table 1, entry 4) to 68% using the IMes-ligand (Table 4, entry 2) in CH2Cl2. Decreasing the amount of base and increasing the equivalents of diazonium salts did not have a beneficial effect (entries 3 and 4). With the optimized reaction conditions, the scope of the reaction was probed as shown in Scheme 26.
49
Results and Discussion
50
The formation of substituted azobenzofurans 32 can be performed in moderate to high yields with electron-donating groups at the alkyne 25, such as OMe or Me, and with diazonium salts 34 having various substituents. The highest yield was observed when reacting OMe-substituted alkyne 25OMe with the non-substituted diazonium salt 34H (88%). A
comparable yield was obtained when reacting the Me-substituted alkyne 25Me with the
non-substituted diazonium salt 34H to azobenzofuran 32Me,H (78%) but the reaction time
almost doubled from 16 hours to 27 hours.
It turned out that the more electron-poor the triple bond of the alkyne is, the longer the reaction times are required for full conversion with reaction times up to 21 days for the F-substituted alkyne 25F. The yields dropped significantly with the –I-effect at the alkyne and with the
F-substituted alkyne 25F the desired products were only observed in traces with the Me- and
F-substituted diazonium salts.
There are two competing reactions that impact the yield negatively: i) the formation of benzofuran 41Me which can be observed with longer reaction times due to protodeauration of
the gold complex possibly by the presence of water at ambient conditions, and ii) the formation of the “open” azo compound 42 due to electrophilic aromatic substitution which has already been identified before (see Scheme 20). Analogous side products as 42 could be observed for almost every reaction as a second yellow / orange spot lower on the TLC plates which becomes more intense when reacting diazonium salts with strong electron-withdrawing groups, such as CF3, but was only isolated for the combination Me-substituted alkyne 25Me
and non-substituted diazonium salt 34H. Furthermore, the isolation of the desired compounds
by flash column chromatography had been challenging due to the almost identical Rf -value of the corresponding benzofurans 37 and azobenzofurans 32. For some compounds an additional second fraction with mixtures of product and side products were isolated, which could slightly increase the yield but the observed and reported trend for the compounds remains the same.
51
Conclusions
2.3)
Conclusions
In this chapter, a light-mediated gold-catalyzed reaction was explored where the same starting materials lead to different products with and without irradiation under ambient conditions. When irradiating alkyne 25 and diazonium salt 34, arylative coupling provides substituted benzofurans 37 in moderate yields under N2-extrusion. Without irradiation, the same starting materials were converted into substituted azobenzofurans 32 in moderate to high yields under C-N-bond formation with N2-retention (see Scheme 27). A series of compounds were isolated after optimization for both reaction types.
Scheme 27: Overview of the divergence in gold catalysis.
Irradiation experiments demonstrate, that a pre-activation of the gold(I) catalyst caused by the addition of diazonium salt 34Me before the coordination to substrate 25 is not feasible in the
present case. The isolation of a vinyl gold(I) complex 46Me and related stoichiometric
experiments with diazonium salt 34H confirm the hypothesis of a possible common
intermediate.
Theoretical studies show, that the colorless vinyl gold(I) complex 46Me,Ph3P can form an
Electron-Donor-Acceptor-Complex with the colorless diazonium salt 34H which allows a photochemical activation for C-C-bond
formation with a charge transfer from the PhN2+ fragment to the vinyl gold(I) complex without the need of an additional photo(redox) catalyst and a prior change in oxidation state. However, in case of arylative coupling a subsequent activation of the vinyl gold(I) complex 46Me,Ph3P can not be ruled out regarding
this experiments.
Figure 10: Structural depictions of fully optimized geometries of
52
2.4)
Author Contributions and Acknowledgements
Preliminary work related to azobenzofurans was done by Dr. René Döpp and Dr. Martin Ackermann but is referenced in the text. NMR measurements were performed under the supervision and with assistance of Ing. Pieter van der Meulen and Dr. Johan Kemmink. Crystallographic measurements were performed and evaluated by Dr. Frank Rominger and Folkert de Vries. DFT calculations were done by Dr. Johannes E. M. N. Klein with the help of Dr. Maximilian F. S. J. Menger. We thank Prof. Dr. A. J. Minnaard for providing access to a photo reactor.
2.5)
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