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Synlett 2024; 35(17): 1965-1975
DOI: 10.1055/s-0042-1751513
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Synthesis of Heterocycles by a C–C Cross-Coupling/Alkyne-Carbonyl-Metathesis Strategy

Peter Langer∗
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   URL: http://www.langer.chemie.uni-rostock.de/
b   Leibniz-Institut für Katalyse an der Universität Rostock e. V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
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Dedicated to Dr. Peter Ehlers on the occasion of his 40th birthday

Abstract

The present article presents a personal account on the synthesis of heterocycles by the combination of regioselective Pd-catalyzed cross-coupling reactions of polyhalogenated heterocycles, i.e., Suzuki–Miyaura and Sonogashira reactions, with alkyne-carbonyl-metathesis (ACM) reactions. The products, which show interesting optical, electronic or medicinal properties, are not readily available by other methods.


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Key words

catalysis - cross-coupling - metathesis - heterocycles - palladium - regioselectivity - 1 Introduction - 2 6-Azaullazines and Pyrrolo[1,2-a]naphthyridines - 3 Dibenzoacridines - 4 Azapyrenes - 5 Naphthothiophenes - 6 Imidazo[1,2-a]benzoazepines - 7 Dibenzotropones - 8 Conclusions

Biographical Sketch

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Peter Langer was born in Hannover (Germany) in 1969. He studied chemistry at the University of Hannover and at the Massachusetts Institute of Technology (MIT), and received his Diploma under the guidance of Prof. Dietmar Seyferth in March 1994. In February 1997, he obtained his Ph.D. (Dr. rer. nat.) under the supervision of Prof. H. Martin R. Hoffmann at the University of Hannover. After postdoctoral studies with Prof. Steven V. Ley, FRS (1997–1998, Cambridge, UK), Peter moved to the University of Göttingen where he started his independent research associated with Prof. Armin de Meijere. He completed his habilitation in July 2001 and became private docent. In April 2002, he took a permanent position as a full professor (C4) at the University of Greifswald. In December 2004, Peter moved to a new position as a full professor (C4) at the University of Rostock. Prof. Langer is the co-author of more than 790 research papers and reviews. He has received the following awards and scholarships: Studienstiftung des deutschen Volkes, Promotionsstipendium des Fonds der Chemischen Industrie, Feodor-Lynen-Stipendium, Liebig-Stipendium, and Heisenberg-Stipendium. He has also been awarded honorary doctorates, honorary professorships and medals from various universities. Peter is an elected member of the Academy of Sciences of the Republic of Armenia and of the Academy of Sciences of Pakistan. He received the civil award ‘Sitara-i-Quaid-i-Azam’ from the President of the Islamic Republic of Pakistan.

1

Introduction

Ring-closing metathesis (RCM) represents nowadays an important and well-established method in organic chemistry.[1] My first contact with RCM took place at the University of Göttingen in the year 2000, where I did my habilitation (assistant professorship) in the group of Prof. Armin de Meijere at that time. One year earlier, we had developed in my group a new synthesis of γ-alkylidenebutenolides based on cyclization reactions of 1,3-dicarbonyl dianions and 1,3-bis(silyl enol ethers) with oxalic acid derivatives. The combination of this methodology with RCM reactions allowed us to prepare bicyclic butenolides containing a medium-sized ring moiety.[2a] In fact, at that time, RCM was still a relatively new methodology and I was happy (and also a little bit surprised) to see that the Grubbs I catalyst worked very well on our systems. In the following years, I sporadically came across RCM reactions, but this reaction never became an independent project in my group.[2] In fact, I stayed away from this field because of high competition. Starting in 2005, during which time I was already a full professor at the University of Rostock, my students and I started to develop regioselective[3] Pd-catalyzed cross-coupling reactions with special emphasis on their application to polyhalogenated heterocycles.[4] Later, we investigated the combination of such reactions with cyclizations by twofold Buchwald–Hartwig reactions,[5] hydroamination reactions,[6] and cycloisomerizations.[7] [8]

In the context of our studies related to cycloisomerization reactions, we also became more and more interested in the synthesis of new heterocyclic core structures and, last but not the least, in their optical, electrochemical and electronic properties. In 2017, Sebastian Boldt, a young first year M.Sc. student, carried out his advanced laboratory course in organic chemistry in my group. In fact, his work turned out to be very fruitful. In a short period of time, Sebastian managed to develop a synthesis of 6-azaullazines by combination of Pd-catalyzed cross-coupling with cycloisomerization reactions.[9] These compounds contain a pyrrole and a pyridine moiety and constituted at that time a new heterocyclic core structure. In general, nitrogen-doped polycyclic aromatic hydrocarbons (PAHs) are of considerable current interest in materials science. For example, they are promising OLED materials because of their physical properties (fluorescence, narrow band gap and others).

Our synthesis of 6-azaullazines is shown in Scheme [1]. Bromination of 4-aminopyridine (1) gave 4-amino-3,5-dibromopyridine (2). An acid-mediated Clauson–Kaas reaction afforded pyrrole 3 which was subsequently transformed into 4-(N-pyrrolyl)-3,5-dialkynylpyridine 4a by Sonogashira reaction with phenylacetylene. Subsequently, Sebastian investigated suitable conditions for the twofold cycloisomerization to give 6-azaullazine 5. After much experimentation, the best yield (78%) was obtained when p-toluenesulfonic acid (PTSA) was employed (xylene, 120 °C, 24 h).

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Scheme 1 Synthesis of 5 and 8a. Conditions: i, NBS (2.5 equiv.), CH2Cl2, 24 h; ii, acetic acid, reflux, 24 h; iii, alkyne (3 equiv.), PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), CataCXium® A (CataCXium® A = PAd2 nBu, 10 mol%), NEt3 (6 equiv.), MeCN, 24 h, 70 °C; iv, PTSA, xylene, 120 °C, 24 h; v, 6a (TFAA, 15 equiv.), 170 °C, Cu2CO3(OH)2 (0.5 equiv.), K2CO3 (2.5 equiv.), 1,2-dichlorobenzene, 1 h.

Scientific progress is sometimes achieved by serendipity. This occurred to me several times during my academic career. During the optimization of the synthesis of 5, Sebastian studied many Brønsted and Lewis acids. One day, he also planned to use trifluoroacetic acid (TFA) and took a bottle with a hand-written label ‘TFA’ from the shelf. Unfortunately, this reagent failed to deliver 5 under various conditions. However, under forcing conditions (170 °C, 1,2-dichlorobenzene), he was able to isolate a small amount of an unexpected product. Sebastian was lucky to obtain a crystal and soon found out that the product turned out to be 6-azaullazine 8a containing a CF3 moiety and a benzoyl substituent.

At this point, Sebastian had two interesting findings in his hand, namely, suitable conditions for the synthesis of 6-azaullazine 5 in good yield and the isolation of a small amount of the unexpected product 8a. As Sebastian had to leave our group to prepare for his exams and to continue other courses, we decided together that Sebastian would later study the scope of the reaction leading to 5. In the meantime, Silvio Parpart, a Ph.D. student in my group, was given the task of further dealing with the formation of 8a.

First, Silvio extensively studied the literature and then suggested that the formation of 8a might be explained by initial acylation of 4a to give 7, acid-mediated cyclization by an alkyne-carbonyl-metathesis (ACM) reaction of the carbonyl group with the alkyne (intermediate A) and subsequent cycloisomerization. In many cases, ACM reactions proceed, similarly to RCM, by a sequence of formal [2+2] and subsequent retro [2+2] cycloadditions.[10] In special cases, hydrolysis of the alkyne to a ketone and subsequent aldol condensation might also be possible. In most cases, ACM reactions are catalyzed by acids or Lewis acids.

In the context of his studies, Silvio found out that the bottle, which was labeled ‘TFA’ and had been used earlier by Sebastian Boldt, in reality did not contain trifluoroacetic acid (TFA), but instead trifluoroacetic anhydride (TFAA). Therefore, a new bottle of TFAA was purchased and used. It was then found that treatment of 4a with trifluoroacetic anhydride (6a) (TFAA, 1 equiv.) at 70 °C resulted in clean acylation of position 2 of the pyrrole moiety of 4a to give ketone 7 in 92% yield (toluene, 1 h). As mentioned above, ACM reactions are catalyzed by Brønsted or Lewis acids. After a thorough screening of various catalysts, Silvio found that 4a could be directly transformed into 6-azaullazine 8a in up to 75% yield when the reaction was carried out using an excess of TFAA (15 equiv.) in the presence of Cu2CO3(OH)2 (0.5 equiv.) and K2CO3 (2.5 equiv.) in 1,2-dichlorobenzene under forcing conditions (170 °C).[11]

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Scheme 2 Synthesis of 8b–t. Conditions: For 8a–r (R ≠ Me): i, 6a–c (15 equiv.), 170 °C, Cu2CO3(OH)2 (0.5 equiv.), K2CO3 (2.5 equiv.), 1,2-dichlorobenzene, 1 h; for 8s,t (R = Me): ii, 1) 6d (15 equiv.), BF3·OEt2, CH2Cl2, 1 h, 0 to 20 °C; 2) Ag2CO3 (0.5 equiv.), K2CO3 (2.5 equiv.), 1,2-dichlorobenzene, 170 °C, 1 h.

# 2

6-Azaullazines and Pyrrolo[1,2-a]naphthyridines

Having suitable reaction conditions in hand, Silvio was able to show that the new methodology was quite general and allowed for the synthesis of a variety of unsymmetrical 6-azaullazines. The reactions of 4a–m with electron-poor, fluorinated anhydrides 6a–c afforded 6-azaullazines 8a–t in 25–96% yields (Scheme [2]).[11] The yields decreased in the presence of electron-withdrawing substituents attached to the phenyl ring (e.g., 8d,e). Due to its lower reactivity, acetic anhydride was not able to directly react with 4a. However, the reaction of 4d,g with acetic anhydride in the presence of BF3·OEt2 at 0 °C afforded the corresponding acetylated intermediates, which were isolated as inseparable mixtures of regioisomeric 2-acetylpyrroles (main product) and 3-acetylpyrroles (side product) in moderate yields (54–59%). Unfortunately, the subsequent ACM reaction did not work under the conditions which were employed for the synthesis of products 8a–r. However, replacement of TFA by para-toluenesulfonic acid (PTSA) together with Ag2CO3 afforded azaullazines 8s,t in 41% and 87% yields which correspond to 25% and 47% overall yields, respectively. The presence of alkyl substituents directly located on the alkyne proved to be unsuccessful. All the compounds are fluorescent with emission maxima around 600 nm and quantum yields up to 10%. The highest emission wavelength is observed for compound 8c having a push–pull substitution pattern. The emission wavelengths of 6-azaullazines 8 were higher and the quantum yields were lower compared to those of symmetrical derivatives, such as 5.

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Scheme 3 Synthesis of 10a–k. Conditions: For 10a–g (R = CF3): i, TFAA, xylene, 140 °C, 6 h, followed by evaporation of volatiles and addition of PTSA in xylene, 140 °C, 1 h; for 10h–k (R = Me): ii, 1) BF3⋅OEt2, CH2Cl2, 20 °C, 8 h; 2) MsOH, 40 °C, 4 h.
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Scheme 4 Synthesis of 12a–i. Conditions: TFAA (15 equiv.), xylene, 140 °C, 6 h, followed by evaporation of volatiles and addition of PTSA (15 equiv.) in xylene, 140 °C, 1 h; for 12d: 65 °C for the second step.
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Scheme 5 Synthesis of 17a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (3 equiv.), Pd(OAc)2 (10 mol%), SPhos (20 mol%), K3PO4 (4 equiv.), THF/H2O (8:1), 65 °C, 22 h; iii, MSA (5.0 equiv.), HFIP, 60 °C, 3 h.

Annika Flader in my group developed a synthesis of pyrrolo[1,2-a]naphthyridines based on a combination of Pd-catalyzed cross-coupling with cycloisomerization reactions.[12] Based on this work, Marian Blanco Ponce together with Silvio Parpart developed a synthesis of two regioisomeric series of pyrrolo[1,2-a]naphthyridines based on ACM reactions. The reaction of TFAA with 3-alkynyl-4-pyrrolylpyridines 9a–g afforded pyrrolo[1,2-a][1,6]naphthyridines 10a–g in 49–81% yields (Scheme [3]).[13] In general, the yields were very good and only dropped in the case of product 10d containing a methoxy group. This result was surprising as it was not expected based on the high yield obtained for 6-azaullazine 8c (vide supra). In fact, electron-donating substituents were expected to stabilize cationic intermediates. In contrast to the synthesis of 6-azaullazines, the employment of acetic anhydride instead of trifluoroacetic anhydride afforded products 10h–j in very good yields (89–95%). The presence of alkyl substituents, directly attached to the alkyne, were not tolerated.

The reactions of 3-alkynyl-2-pyrrolylpyridines 11a–i with TFAA afforded pyrrolo[1,2-a][1,8]naphthyridines 12a–i in 20–69% yields (Scheme [4]).[13] In general, the yields were moderate to good and generally turned out to be lower than the yields of regioisomeric products 10a–g.

Pyrrolo[1,2-a]naphthyridines were previously prepared by other methods. However, these strategies often require complex starting materials, harsh reaction conditions or uneconomic catalyst systems.[14] We did not study direct applications of compounds 10. However, pyrrolo[1,2-a]naphthyridines represent drug-like molecules and a variety of medicinal applications have been reported for related indolizines.[15]


# 3

Dibenzoacridines

Erich Ammon, Annika Flader and Lars Ohlendorf, all Ph.D. students in my group, studied the synthesis of dibenzo[c,h]acridines and dibenzo[a,j]acridines by a combination of Pd-catalyzed cross-coupling with cycloisomerization reactions.[16] Based on this work, we had the idea to apply ACM reactions for the synthesis of dibenzoacridines. The Sonogashira reaction of 2,3,5,6-tetrabromopyridine (13a) with phenylacetylene regioselectively afforded 2,6-dialkynyl-3,5-dibromopyridine 14a (Scheme [5]). The required carbonyl group for the ACM reaction was directly introduced by a Suzuki–Miyaura reaction of 14a with (2-formylphenyl)boronic acid (15a) to give ACM precursor 16a.[17] Subsequent ACM reaction via intermediate A afforded dibenzo[a,j]acridine 17a in 97% yield. The best yield was obtained when the ACM reaction was carried out using mesylic acid (MSA) and hexafluoroisopropanol (HFIP) as the solvent.

The synthesis proved to be rather general and dibenzo[a,j]acridines 17a–k were successfully prepared in mostly very good to excellent yields (Figure [1]).[17] The yields dropped in the case of employment of an annulated thiophene unit (product 17h) or when utilizing 2-acetyl- rather than (2-formylphenyl)boronic acid (product 17k), due to the lower electrophilicity of the ketone as compared to the aldehyde.

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Scheme 6 Synthesis of 20a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (3.0 equiv.), Pd(PPh3)4 (5 mol%), K3PO4 (4.0 equiv.), THF/H2O (4:1), 65 °C, 22 h; iii, PTSA (20 equiv.), HFIP, 60 °C, 6 h.

Dibenzo[c,h]acridine 20a, a regioisomer of 17a, was prepared from 3,5-dibromo-2,6-dichloropyridine (13b). Sonogashira reaction of 13b with phenylacetylene took place at positions 3 and 5, due to the better leaving group ability of bromide as compared to chloride (Scheme [6]).[16] Suzuki reaction of 18a with 15a gave 2,6-di(2-formylphenyl)-3,5-dialkynylpyridine 19a. Subsequent ACM reaction, using PTSA instead of MSA, afforded the desired product 20a.[17]

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Figure 1 Structures of products 17a–k

Likewise, dibenzo[c,h]acridines 20a–e were prepared (Figure [2]).[17] The yields dramatically dropped in the presence of a methoxy group attached to the phenyl group, presumably due to the electron-donating effect of the methoxy group which results in a reduced electrophilicity of the aldehyde. A number of dibenzoacridines 17 and 20 were studied by steady-state absorption and fluorescence spectroscopy and by time-resolved emission measurements. The optical properties are mainly governed by the dibenzoacridine scaffolds. The attached benzoyl moieties have only a small effect on the absorption and emission properties. However, some of the compounds exhibit a charge transfer state.

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Figure 2 Synthesis of 20a–e
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Scheme 7 Synthesis of 24a and 25a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (1.6 equiv.), Pd(PPh3)4, K2CO3, dioxane/water, 90 °C; iii, TFAA (150.0 equiv.), 72 °C, 16 h; iv, PTSA (30.0 equiv.), xylene, 120 °C, 16 h.

# 4

Azapyrenes

In 2020, Ricardo Molenda, a Ph.D. student in my group, developed, based on the combination of Pd-catalyzed cross-coupling with cycloisomerization reactions, a synthesis of 2-azapyrenes which represented at that time a new heterocyclic core structure.[18] Later, Sebastian Boldt, also a Ph.D. student in my group (see also the Introduction section), developed a synthesis of unsymmetrical 2-azapyrene derivatives by application of ACM reactions. The Sonogashira reaction of phenylacetylene with bis(triflate) 21a, prepared from 4-chloro-3,5-dihydroxypyridine, afforded 3,5-dialkynyl-4-chloropyridine 22a in 97% yield (Scheme [7]).[19] Suzuki–Miyaura reaction of the latter with (2-formylphenyl)boronic acid (15a) gave 3,5-dialkynyl-4-(2-formylphenyl)pyridine 23a in 86% yield. Treatment of 23a with TFAA (reflux) afforded azaphenanthrene 24a in 93% yield. Under these conditions, only the ACM reaction took place (via intermediate A), while the cycloisomerization did not occur and the second alkynyl unit remained unattacked. In contrast, reaction of 23a with PTSA in xylene at 120 °C resulted in formation of 2-azapyrene 25a in 96% yield. Formation of this product can be explained by initial generation of product 24a which subsequently underwent, under the more forcing conditions employed, a cycloisomerization to give the final product.

A number of 2-azaphenanthrenes were successfully prepared (for a selection of products, see Figure [3]).[19] Both electron-donating and electron-withdrawing substituents were tolerated at various positions of the benzoyl group and of the heterocyclic core structure. Employment of aliphatic alkynes, such as 1-heptyne, instead of arylacetylenes proved to be possible and proceeded with acceptable yields (e.g., product 24e).

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Figure 3 Structures of products 24b–e

A variety of 2-azapyrenes were successfully prepared (for selected examples, see Figure [4]).[19] A variety of electron-donating and electron-withdrawing substituents were again tolerated at various positions of the benzoyl group and of the heterocyclic core structure. However, in contrast to the synthesis of azaphenanthrenes 24, aliphatic alkynes could not be successfully employed.

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Figure 4 Structures of products 25b–k
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Scheme 8 Synthesis of 31a and 32a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (2 equiv.), Pd2dba3 (5 mol%), SPhos (10 mol%), K3PO4 (2 equiv.), toluene, 110 °C, 24 h; iii, PTSA (30.0 equiv.), toluene, 100 °C, 5 h; iv, PTSA (30.0 equiv.), xylene, 140 °C, 24 h

Based on our experiences with the synthesis of 2-azapyrenes, Arpine Vardanyan, a Ph.D. student from Yerevan State University (Armenia), developed a synthesis of isomeric 1-azapyrenes based on cycloisomerization reactions.[20] Two years later, Arpine also studied the application of ACM reactions for the synthesis of 1-azapyrenes (Scheme [8]).[21] The Sonogashira reaction of the bis(triflate) 26 of 3-chloro-2,4-dihydroxypyridine with phenylacetylene afforded 2,4-dialkynyl-3-chloropyridine 27a in excellent yield. The regioselectivity can be explained by the better leaving group ability of triflate as compared to chloride. The use of the bis(triflate) instead of the corresponding dibromide was simply a result of its easier availability. The Suzuki–Miyaura reaction of 27a with (2-formylphenyl)boronic acid (15a) afforded 2,4-dialkynyl-3-(2-formylphenyl)pyridine 28a in 63% yield. Due to the unsymmetrical structure of 28a, two different products are, in principle, possible for the ACM reaction. Treatment of 28a with PTSA (30 equiv.) in toluene (100 °C, 5 h) afforded a separable mixture of products 29a and 30a in 67% and 26% isolated yields, respectively. Elevation of the temperature (xylene, 140 °C) and prolongation of the reaction time (24 h) induced cycloisomerization and transformed 29a and 30a into 1-azapyrenes 31a and 32a in 93% and 94% yield, respectively.

The reaction proved to be quite general (for selected products, see Figure [5]).[21] The photophysical and electrochemical properties of the 1-azapyrenes were extensively studied and the results were compared with theoretical results. These studies showed that the substituted electron-withdrawing benzoyl group located in the K-region of the 1-azapyrene plays a crucial role for the modulation of the photophysical and electrochemical properties by reducing the HOMO–LUMO gap and enhancing the electron-accepting ability, as compared to symmetrical 1-azapyrenes not containing a benzoyl group.[20] However, the introduction of a benzoyl group on the azapyrene framework causes a decrease of the fluorescence intensity, while the presence of π-donating groups increase the quantum yields by a factor 3. Having strong π-donating methoxy and N,N-dimethylamino substituents, products 31b and 32b exhibit strong ICT character, which was also confirmed by DFT/TD-DFT calculations, solvatochromism and time-resolved fluorescence studies. Moreover, benzoyl-substituted 1-azapyrenes have been proved to serve as acid-responsive materials and their deprotonation is reversible.

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Figure 5 Structures of products 31b–e and 32b–e

# 5

Naphthothiophenes

Maryan Sobhani, a Ph.D. student and DAAD scholar from Iran, studied the application of the ACM reaction to the synthesis of two regioisomeric series of naphthothiophenes.[22] The Suzuki–Miyaura reaction of 2,3-dibromothiophene (33) with (2-formylphenyl)boronic acid (15a) and subsequent Sonogashira reaction with phenylacetylene afforded 34a (Scheme [9]). Subsequent ACM reaction in the presence of PTSA (toluene, 100 °C, 1 h) afforded naphtho[1,2-b]thiophene 35a.

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Scheme 9 Synthesis of 35a. Conditions: i, 15a (1.3 equiv.), PdCl2(PPh3)2 (7 mol%), K2CO3 (2.5 equiv.), DMF/EtOH (4:1), 65 °C, 8–10 h; ii, phenylacetylene (1.2 equiv.), PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), l-proline (15 mol%), Cs2CO3 (1.5 equiv.), 100 °C, 12–14 h; iii, PTSA (15.0 equiv.), toluene, 100 °C, 1 h.

The reaction proved to be rather general and substituents were tolerated at various positions. A selection of the products is shown in Figure [6].[22] It is worth noting that product 35e, derived from (2-acetylphenyl)boronic acid, was obtained in good yield, despite the lower reactivity of the ketone as compared to the aldehyde group.

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Figure 6 Structures of products 35b–f

A change of the order of reactions allowed for the synthesis of regioisomeric naphtho[2,1-b]thiophenes. The Sonogashira reaction of 2,3-dibromothiophene (33) with phenylacetylene and subsequent Suzuki–Miyaura reaction with 15a afforded 36a (Scheme [10]).[22] Subsequent ACM reaction in the presence of PTSA (toluene, 100 °C, 1 h) gave the desired product 37a.

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Scheme 10 Synthesis of 37a. Conditions: i, phenylacetylene (1.2 equiv.), PdCl2(PPh3)2 (6 mol%), CuI (5 mol%), Et3N (3.5 equiv.), DMF (2 mL), 70 °C, 4–5 h; ii, 15a (1.2 equiv.), PdCl2(PPh3)2 (8 mol%), K2CO3 (3 equiv.), EtOH (0.5 mL) 100 °C, 8–10 h; iii, PTSA (15.0 equiv.), toluene, 100 °C, 1 h.

A number of derivatives were successfully prepared (Figure [7]).[22] Both electron-donating and electron-withdrawing substituents were again tolerated. A methyl group instead of a hydrogen atom could again be successfully installed in the central ring by using (2-acetylphenyl)- instead of (2-formylphenyl)boronic acid during the synthesis. In addition, 2,3-dibromobenzothiophene instead of 2,3-dibromothiophene (33) could be successfully employed as a starting material which allowed the preparation of compound 37e.

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Figure 7 Structures of products 37b–e

Thiophene-fused π-conjugated systems, such as naphthothiophenes, show promising optoelectronic properties and photochemical stability and are interesting as electronic devices for OLED applications.[23] In addition, naphthothiophenes have been reported to be promising anti-cancer compounds.[24]


# 6

Imidazo[1,2-a]benzoazepines

Maryan Sobhani also developed an application of ACM reactions for the synthesis of imidazo[1,2-a]benzoazepines. The N-alkylation of benzimidazole (38a) with 2-bromobenzylic bromide afforded 39a (Scheme [11]).[25] Formylation by deprotonation of carbon C-2 of the benzimidazole moiety and subsequent addition of dimethyl formamide (DMF) gave 2-formylbenzimidazole 40a which was then transformed into ACM precursor 41a by Sonogashira reaction with phenylacetylene. A subsequent ACM reaction (PTSA, toluene, 100 °C, 3 h) afforded the desired imidazo[1,2-a]benzoazepine 42a.

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Scheme 11 Synthesis of 42a. Conditions: i, KOH (4 equiv.), DMSO, 20 °C, 5 h; ii, 1) LDA (1.1 equiv.), THF; 2) DMF (1.5 equiv.), –78 °C to 20 °C; iii, phenylacetylene (2.0 equiv.), Pd(CH3CN)2Cl2 (6 mol%), CuI (4 mol%), diisopropylamine (3 equiv.), X-Phos (12 mol%), 1,4-dioxane, 35 °C, 12 h; iv, PTSA (15 equiv.), toluene, 100 °C, 3 h.

The preparative scope was again studied in detail. A selection of products is shown in Figure [8].[25] Both electron-donating and electron-withdrawing substituents were tolerated at various positions of the benzoyl group and of the heterocyclic core structure. Although applications of compounds 42 were not investigated by us, they are of interest in the field of medicinal chemistry. In 2005, inspired by the structures of the antihistamines mirtazapine, desloratadine, and loratadine, a spirocyclic norpiperidine imidazoazepine was developed as a selective and nonsedating H1 antihistamine.[26]

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Figure 8 Structures of products 42b–j

# 7

Dibenzotropones

Maryan Sobhani also developed an application of ACM reactions to the synthesis of two regioisomeric series of dibenzotropones.[27] Sonogashira reaction of 2-bromobenzoyl chloride (43) with phenylacetylene gave alkynylarylketone 44a (Scheme [12]). Suzuki–Miyaura reaction of the latter with (2-formylphenyl)boronic acid (15a) afforded biphenyl derivative 45a, which was then transformed into the desired product, 5H-dibenzo[a,c]cyclohepten-5-one 46a, by a PTSA-mediated ACM reaction. This reaction was at that time, to the best of our knowledge, the first application of an ACM reaction to the synthesis of a seven-membered ring.

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Scheme 12 Synthesis of 46a. Conditions: i, PdCl2(PPh3)2 (6 mol%), Cul (4 mol%), NEt3, toluene, 20 °C, 12–15 h; ii, Pd(PPh3)4 (5 mol%), 1,4-dioxane, K2CO3, H2O, 65 °C; iii, PTSA (15.0 equiv.), HFIP, 60 °C, 3 h.

A variety of substituted 5H-dibenzo[a,c]cyclohepten-5-ones were successfully prepared (for selected examples, see Figure [9]).[27] Both electron-donating and electron-withdrawing substituents were tolerated at various positions of the benzoyl group and of the heterocyclic core structure. The presence of electron-withdrawing fluorine atoms attached to the dibenzotropone system resulted in a moderate decrease of the yields.

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Figure 9 Structures of products 46b–f

The synthesis of 5H-dibenzo[a,d]cyclohepten-5-ones 52, regioisomers of products 46, required a different strategy. Reaction of 2-bromobenzoyl hydrazide (48) with salicylic aldehyde (47) afforded adduct 49 (Scheme [13]).[27] Treatment of the latter with Pb(OAc)4 gave 2-formyl-2′-bromobenzophenone (50), which was transformed into alkyne 51a by Sonogashira reaction with phenylacetylene. Subsequent ACM reaction of 51a afforded the desired product 52a.

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Scheme 13 Synthesis of 52a. Conditions: i, EtOH, reflux; ii, Pb(OAc)4, THF, reflux; iii, phenylacetylene (1.2 equiv.), PdCl2(PPh3)2 (5 mol%), Cul (5 mol%), PPh3 (10 mol%), NEt3, 70 °C, 12–15 h; iv, PTSA (5.0 equiv.), toluene, 80 °C, 6 h.

In general, the yields of dibenzotropones 52 were lower than those of their corresponding isomers 46. However, a number of products 52 were successfully prepared (Figure [10]).[27] Both electron-donating and electron-withdrawing substituents were tolerated on the benzoyl group. The presence of the electron-withdrawing CF3 group (product 52c) resulted in a moderate decrease of the yield, while the presence of a fluoride only resulted in a minor decrease of the yield (product 52d). A drastic decrease of the yield was observed for product 52e which contains an aliphatic rather than an aromatic substituent attached to the carbonyl group. Physical or medicinal applications of compounds 46 and 52 were not studied by us. However, benzotropones are present in a variety of natural products and have been reported to show a broad spectrum of pharmacological activities.[28]

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Figure 10 Structures of products 52b–e

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Conclusions

The present accounts aims to highlight our efforts to prepare various heterocycles by combination of regioselective Suzuki–Miyaura and Sonogashira coupling reactions of polyhalogenated heterocycles with alkyne-carbonyl-metathesis (ACM) reactions. The common structural feature of the products is the presence of a benzoyl substituent attached to the heterocyclic core structure. The substitution patterns of the (in all cases) unsymmetrical products is not available by cycloisomerization reactions. Variation of the substitution pattern of the heterocyclic products allows adjustment and optimization of their optical, electronic or medicinal properties.


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Conflict of Interest

The author declares no conflict of interest.

Acknowledgment

I am very grateful to Dr. Peter Ehlers, senior research associate and group leader in my team, who greatly contributed to the project presented in this account. In addition, I am very grateful to my former Ph.D. students who carried out all the work in the laboratory. Their names are (in alphabetical order): Drs Erich Ammon, Marian Blanco Ponce, Sebastian Boldt, Rúben M. Figueira de Abreu, Anna Frey, Silvio Parpart, Maryan Sobhani, and Arpine Vardanyan. In addition, the contributions of several B.Sc. and M.Sc. students is gratefully acknowledged.


Corresponding Author

Peter Langer
Institut für Chemie, Universität Rostock
Albert-Einstein-Str. 3a, 18059 Rostock
Germany   

Publication History

Received: 31 August 2023

Accepted after revision: 21 September 2023

Article published online:
22 February 2024

© 2024. Thieme. All rights reserved

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Scheme 1 Synthesis of 5 and 8a. Conditions: i, NBS (2.5 equiv.), CH2Cl2, 24 h; ii, acetic acid, reflux, 24 h; iii, alkyne (3 equiv.), PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), CataCXium® A (CataCXium® A = PAd2 nBu, 10 mol%), NEt3 (6 equiv.), MeCN, 24 h, 70 °C; iv, PTSA, xylene, 120 °C, 24 h; v, 6a (TFAA, 15 equiv.), 170 °C, Cu2CO3(OH)2 (0.5 equiv.), K2CO3 (2.5 equiv.), 1,2-dichlorobenzene, 1 h.
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Scheme 2 Synthesis of 8b–t. Conditions: For 8a–r (R ≠ Me): i, 6a–c (15 equiv.), 170 °C, Cu2CO3(OH)2 (0.5 equiv.), K2CO3 (2.5 equiv.), 1,2-dichlorobenzene, 1 h; for 8s,t (R = Me): ii, 1) 6d (15 equiv.), BF3·OEt2, CH2Cl2, 1 h, 0 to 20 °C; 2) Ag2CO3 (0.5 equiv.), K2CO3 (2.5 equiv.), 1,2-dichlorobenzene, 170 °C, 1 h.
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Scheme 3 Synthesis of 10a–k. Conditions: For 10a–g (R = CF3): i, TFAA, xylene, 140 °C, 6 h, followed by evaporation of volatiles and addition of PTSA in xylene, 140 °C, 1 h; for 10h–k (R = Me): ii, 1) BF3⋅OEt2, CH2Cl2, 20 °C, 8 h; 2) MsOH, 40 °C, 4 h.
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Scheme 4 Synthesis of 12a–i. Conditions: TFAA (15 equiv.), xylene, 140 °C, 6 h, followed by evaporation of volatiles and addition of PTSA (15 equiv.) in xylene, 140 °C, 1 h; for 12d: 65 °C for the second step.
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Scheme 5 Synthesis of 17a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (3 equiv.), Pd(OAc)2 (10 mol%), SPhos (20 mol%), K3PO4 (4 equiv.), THF/H2O (8:1), 65 °C, 22 h; iii, MSA (5.0 equiv.), HFIP, 60 °C, 3 h.
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Scheme 6 Synthesis of 20a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (3.0 equiv.), Pd(PPh3)4 (5 mol%), K3PO4 (4.0 equiv.), THF/H2O (4:1), 65 °C, 22 h; iii, PTSA (20 equiv.), HFIP, 60 °C, 6 h.
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Figure 1 Structures of products 17a–k
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Figure 2 Synthesis of 20a–e
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Scheme 7 Synthesis of 24a and 25a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (1.6 equiv.), Pd(PPh3)4, K2CO3, dioxane/water, 90 °C; iii, TFAA (150.0 equiv.), 72 °C, 16 h; iv, PTSA (30.0 equiv.), xylene, 120 °C, 16 h.
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Figure 3 Structures of products 24b–e
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Figure 4 Structures of products 25b–k
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Scheme 8 Synthesis of 31a and 32a. Conditions: i, Phenylacetylene (2.2 equiv.), Pd(PPh3)4 (10 mol%), CuI (10 mol%), HN(iPr)2, 30 °C, 45 min; ii, 15a (2 equiv.), Pd2dba3 (5 mol%), SPhos (10 mol%), K3PO4 (2 equiv.), toluene, 110 °C, 24 h; iii, PTSA (30.0 equiv.), toluene, 100 °C, 5 h; iv, PTSA (30.0 equiv.), xylene, 140 °C, 24 h
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Figure 5 Structures of products 31b–e and 32b–e
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Scheme 9 Synthesis of 35a. Conditions: i, 15a (1.3 equiv.), PdCl2(PPh3)2 (7 mol%), K2CO3 (2.5 equiv.), DMF/EtOH (4:1), 65 °C, 8–10 h; ii, phenylacetylene (1.2 equiv.), PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), l-proline (15 mol%), Cs2CO3 (1.5 equiv.), 100 °C, 12–14 h; iii, PTSA (15.0 equiv.), toluene, 100 °C, 1 h.
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Figure 6 Structures of products 35b–f
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Scheme 10 Synthesis of 37a. Conditions: i, phenylacetylene (1.2 equiv.), PdCl2(PPh3)2 (6 mol%), CuI (5 mol%), Et3N (3.5 equiv.), DMF (2 mL), 70 °C, 4–5 h; ii, 15a (1.2 equiv.), PdCl2(PPh3)2 (8 mol%), K2CO3 (3 equiv.), EtOH (0.5 mL) 100 °C, 8–10 h; iii, PTSA (15.0 equiv.), toluene, 100 °C, 1 h.
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Figure 7 Structures of products 37b–e
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Scheme 11 Synthesis of 42a. Conditions: i, KOH (4 equiv.), DMSO, 20 °C, 5 h; ii, 1) LDA (1.1 equiv.), THF; 2) DMF (1.5 equiv.), –78 °C to 20 °C; iii, phenylacetylene (2.0 equiv.), Pd(CH3CN)2Cl2 (6 mol%), CuI (4 mol%), diisopropylamine (3 equiv.), X-Phos (12 mol%), 1,4-dioxane, 35 °C, 12 h; iv, PTSA (15 equiv.), toluene, 100 °C, 3 h.
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Figure 8 Structures of products 42b–j
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Scheme 12 Synthesis of 46a. Conditions: i, PdCl2(PPh3)2 (6 mol%), Cul (4 mol%), NEt3, toluene, 20 °C, 12–15 h; ii, Pd(PPh3)4 (5 mol%), 1,4-dioxane, K2CO3, H2O, 65 °C; iii, PTSA (15.0 equiv.), HFIP, 60 °C, 3 h.
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Figure 9 Structures of products 46b–f
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Scheme 13 Synthesis of 52a. Conditions: i, EtOH, reflux; ii, Pb(OAc)4, THF, reflux; iii, phenylacetylene (1.2 equiv.), PdCl2(PPh3)2 (5 mol%), Cul (5 mol%), PPh3 (10 mol%), NEt3, 70 °C, 12–15 h; iv, PTSA (5.0 equiv.), toluene, 80 °C, 6 h.
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Figure 10 Structures of products 52b–e