Hemetsberger–Knittel and Ketcham Synthesis of Heteropentalenes with Two (1:1), Three (1:2)/(2:1) and Four (2:2) Heteroatoms

: The synthetic methods leading to furo[3,2-b ]pyrroles and thiazolo [5,4-d ]thiazoles are reviewed herein. Furo-, thieno-and seleno [3,2-b ]pyrroles are related to heteropentalenes, containing two heteroatoms in the entire structure, one each per core. The synthetic approach follows the Hemetsberger–Knittel protocol covering three reaction steps—the nucleophilic substitution of halogen-containing aliphatic carboxylic acid esters, Knoevenagel condensation and, ﬁnally, thermol-ysis promoting the intramolecular cyclocondensation to O,N-heteropentalene. The Hemetsberger– Knittel reaction sequence is also known for the preparation of O,N-heteropentalenes with three heteroatoms (2:1) and their sulphur and selen heteroatoms containing structural analogues and bis pyrroles. The synthetic approach towards thiazolo [5,4-d ] thiazoles represents a more straightforward route, according to the Ketcham cyclocondensation. Proceeding with the Ketcham process is more challenging since it occurs stepwise and the formation of by-products is obvious. Thiazolo [5,4-d ]thiazole is a representative of the aromatic heteropentalene with four heteroatoms in the structure—twinned N and S, two for each of the ﬁve-membered rings. The synthetic approaches towards those particular heteropentalnes have been chosen as a consequence of our ongoing research dealing with the design, synthesis and applications of substituted furo [3,2-b ]pyrroles and thiazolo [5,4-d ]thiazole-based derivatives. While the furopyrroles are known for their pharmacological activity, thiazolothiazoles have become of interest to materials science. We are aware that from a “bank” of existing compounds/procedures not all are presented in this review, and we apologise to respective groups whose research have not been objectively included.


Introduction
Annelated [5+5] heterocyclic systems that consist of two-fused, five-membered rings represent a family of heteropentalenes (HPs) [1]. HPs are isoelectronic to pentalenyl dianion (PnDa, Figure 1) [2] with the preserved 10π-electron system since the electron pair/s of heteroatom/s are involved in the conjugation. In combination with the structural planarity and bicyclic motif, HP scaffolds are aromatic [3]. Since the first Ramsden's classification of HPs into four general types (I-IV, Figure 2) in 1977 [4,5], the number of identified 5-5 bicyclic regioisomers with two heteroatoms, one for each core (1:1), has increased dramatically [1,6]. The presence of four heteroatoms in a structure, two per core (2:2), has led to the rise of basic structural prototypes up to sixteen [7]. Undoubtedly, through the addition of more heteroatoms into the bicyclic system and by variations in modes of fusion altogether, including the non-classical heteropentalenes and betaines, the number of possible isoconjugates has reached an uncountable number. Generally, oxygen, sulphur, nitrogen, selenium and tellurium are the most commonly employed as heteroatoms [1][2][3][4][5][6][7], Reactions 2023, 4 255 but a few reports on HPs with phosphorus [8], boron [9] or silicon [10] in the position of heteroatom have recently been published.
Although there is a plethora of HPs permutations, at the same time they represent small-organic-type compounds with an advantage of being easily prepared. The ring clo sure reactions, cyclisations and cycloadditions are obviously performed to obtain a par ticular HP derivative [12][13][14]. With their synthetic availability, in combination with a va riety of advantageous optoelectronic, physicochemical and pharmacological properties HPs are of significant interest in the fields of both academic research and industry.
With respect to our research aims [15,16], together with taking into account the enor mous number of existing derivatives, herein we have highlighted the synthesis of fur [3,2-b]pyrroles (V, Figure 3) using a three-step Hemetsberger-Knittel procedure, and thi azolo [5,4-d]thiazoles (VI, Figure 3) as representative products of the Ketcham reaction While the furo [3,2-b]pyrroles come from a category of O,N-two heteroatoms containing HPs with applications in pharmaceuticals, the thiazolo [5,4-d]thiazole scaffold consists o two thiazole rings containing a combination of four heteroatoms, nitrogen and sulphur in each annelated core and are very important in applied science for the development o optoelectronic devices such as organic photovoltaic cells (OPV and organic field-effec transistors (OFETs). but a few reports on HPs with phosphorus [8], boron [9] or silicon [10] in the position of heteroatom have recently been published. Figure 1. Resonance structures of the pentalenyl dianon (PnDa) as a leading structure for a class of heteropentalenes.
Although there is a plethora of HPs permutations, at the same time they represent a small-organic-type compounds with an advantage of being easily prepared. The ring closure reactions, cyclisations and cycloadditions are obviously performed to obtain a particular HP derivative [12][13][14]. With their synthetic availability, in combination with a variety of advantageous optoelectronic, physicochemical and pharmacological properties, HPs are of significant interest in the fields of both academic research and industry.
With respect to our research aims [15,16], together with taking into account the enormous number of existing derivatives, herein we have highlighted the synthesis of furo [3,2-b]pyrroles (V, Figure 3) using a three-step Hemetsberger-Knittel procedure, and thiazolo [5,4-d]thiazoles (VI, Figure 3) as representative products of the Ketcham reaction. While the furo [3,2-b]pyrroles come from a category of O,N-two heteroatoms containing HPs with applications in pharmaceuticals, the thiazolo [5,4-d]thiazole scaffold consists of two thiazole rings containing a combination of four heteroatoms, nitrogen and sulphur in each annelated core and are very important in applied science for the development of optoelectronic devices such as organic photovoltaic cells (OPV and organic field-effect transistors (OFETs).
For a structural description in combination with the HPs' nomenclature, the general Formula (1) can be applied for recognising the appropriate hetarene [11] according to: hetaryl[m,n-p]hetarene (1) where m,n are numbers of carbon atoms shared by both rings, the p-junction mode reveals the shared bond, hetaryl is the name of a five-membered heterocycle in a prefix, and hetarene is the name of a superior five-membered heterocycle [1,4,6,7,11]. Although there is a plethora of HPs permutations, at the same time they represent a small-organic-type compounds with an advantage of being easily prepared. The ring closure reactions, cyclisations and cycloadditions are obviously performed to obtain a particular HP derivative [12][13][14]. With their synthetic availability, in combination with a variety of advantageous optoelectronic, physicochemical and pharmacological properties, HPs are of significant interest in the fields of both academic research and industry.
With respect to our research aims [15,16], together with taking into account the enormous number of existing derivatives, herein we have highlighted the synthesis of furo [3,2-b]pyrroles (V, Figure 3) using a three-step Hemetsberger-Knittel procedure, and thiazolo [5,4-d]thiazoles (VI, Figure 3) as representative products of the Ketcham reaction. While the furo [3,2-b]pyrroles come from a category of O,N-two heteroatoms containing HPs with applications in pharmaceuticals, the thiazolo [5,4-d]thiazole scaffold consists of two thiazole rings containing a combination of four heteroatoms, nitrogen and sulphur in each annelated core and are very important in applied science for the development of optoelectronic devices such as organic photovoltaic cells (OPV and organic field-effect transistors (OFETs).  Figure 3. Structure of furo [3,2-b]pyrrole (V) as representative of two heteroatoms containing HPs (1:1, each core), achievable through the Hemetsberger-Knittel procedure, and thiazolo [5,4-d]thiazole (VI) from the category of four heteroatom-containing HPs (2:2, two per core) as a product of Ketcham's process, respectively.
Hemetsberger-Knittel synthesis requires readily available starting materials with a wide variety of functional groups and often induces good overall yields. The overall process involves three steps: the initial synthesis of an alkyl azidoacetate 3, followed by a base-promoted Knoevenagel condensation of alkyl azidoacetate 3 and an aromatic aldehyde 4 to form 2-azido-3-arylacrylate 5, and finally the thermolysis of the 2-azido-3-arylacrylate 5 in an intramolecular cyclisation to form the fused pyrrole skeleton 1 (Scheme 1). The major limitation of the Hemetsberger-Knittel process emerged from the use of sodium azide and two potentially explosive intermediates, 3 and 5, in sequence [36].  [3,2-b]pyrrole (V) as representative of two heteroatoms containing HPs (1:1, each core), achievable through the Hemetsberger-Knittel procedure, and thiazolo [5,4-d]thiazole (VI) from the category of four heteroatom-containing HPs (2:2, two per core) as a product of Ketcham's process, respectively.
Hemetsberger-Knittel synthesis requires readily available starting materials with a wide variety of functional groups and often induces good overall yields. The overall process involves three steps: the initial synthesis of an alkyl azidoacetate 3, followed by a basepromoted Knoevenagel condensation of alkyl azidoacetate 3 and an aromatic aldehyde 4 to form 2-azido-3-arylacrylate 5, and finally the thermolysis of the 2-azido-3-arylacrylate 5 in an intramolecular cyclisation to form the fused pyrrole skeleton 1 (Scheme 1). The major limitation of the Hemetsberger-Knittel process emerged from the use of sodium azide and two potentially explosive intermediates, 3 and 5, in sequence [36].
Hemetsberger-Knittel synthesis requires readily available starting materials with a wide variety of functional groups and often induces good overall yields. The overall process involves three steps: the initial synthesis of an alkyl azidoacetate 3, followed by a base-promoted Knoevenagel condensation of alkyl azidoacetate 3 and an aromatic aldehyde 4 to form 2-azido-3-arylacrylate 5, and finally the thermolysis of the 2-azido-3-arylacrylate 5 in an intramolecular cyclisation to form the fused pyrrole skeleton 1 (Scheme 1). The major limitation of the Hemetsberger-Knittel process emerged from the use of sodium azide and two potentially explosive intermediates, 3 and 5, in sequence [36].
The second step of the Hemetsberger-Knittel procedure involves the Knoevenagel condensation of aromatic aldehydes 4 with alkyl azidoacetate 3 to form 2-azido-3-arylacrylates 5 in relatively low yields. Typical yields of 5 have been reported to range from 12% to 65% when five-membered heteroaromatic aldehydes were used [28,39].
The low yields of 5 could be explained [36] due to two primary reasons. First, alkyl azidoacetates 3 decompose in the presence of base, and the decomposition competes with the desired condensation process.
The second reason lies in the hydrolysis of the ester functionality of the alkyl azidoacetate reagent 3, the azido alcohol intermediate and the 2-azido-3-arylacrylate product 5, which is promoted by the hydroxide by-product from the condensation. In the case of the Knoevenagel condensation of furan-2-carbaldehyde and ethyl azidoacetate, the undesired ester hydrolysis product of the azido alcohol intermediate (2-azido-3-hydroxy-3-(furan-2-yl)propanoic acid) 6 has been identified as a side product in yields as high as 40%. In this particular case, this acidic by-product did not undergo dehydration to afford 2-azido-3-(furan-2-yl)acrylic acid ( Figure 4) [36].
The second step of the Hemetsberger-Knittel procedure involves the Knoevenagel condensation of aromatic aldehydes 4 with alkyl azidoacetate 3 to form 2-azido-3-arylacrylates 5 in relatively low yields. Typical yields of 5 have been reported to range from 12% to 65% when five-membered heteroaromatic aldehydes were used [28,39].
The low yields of 5 could be explained [36] due to two primary reasons. First, alkyl azidoacetates 3 decompose in the presence of base, and the decomposition competes with the desired condensation process.
The second reason lies in the hydrolysis of the ester functionality of the alkyl azidoacetate reagent 3, the azido alcohol intermediate and the 2-azido-3-arylacrylate product 5, which is promoted by the hydroxide by-product from the condensation. In the case of the Knoevenagel condensation of furan-2-carbaldehyde and ethyl azidoacetate, the undesired ester hydrolysis product of the azido alcohol intermediate (2-azido-3-hydroxy-3-(furan-2yl)propanoic acid) 6 has been identified as a side product in yields as high as 40%. In this particular case, this acidic by-product did not undergo dehydration to afford 2-azido-3-(furan-2-yl)acrylic acid ( Figure 4) [36]. The third step of the Hemetsberger-Knittel reaction is the thermolysis of the 2-azido-3-arylacrylate 5 in an intramolecular cyclisation to form a fused pyrrole skeleton (Scheme 1). The typical solvents that are used are toluene [18], xylenes [28] or mesitylene [38].

Mechanism of the Hemetsberger-Knittel Synthesis
The mechanism [40] of the Hemetsberger-Knittel reaction proceeds via an azirene intermediate 8. The first step is the thermal degradation of 2-azido-3-arylacrylate 5, generating molecular nitrogen and nitrene 7. Nitrene 7 is believed to be in equilibrium with the azirine intermediate 8. The subsequent step is the insertion of the nitrene into the cyclic ring followed by a final [1,5] hydrogen shift that is accompanied by the final re-aromatisation, forming the pyrrole core of the fused aromatic system 1 (Scheme 2). The third step of the Hemetsberger-Knittel reaction is the thermolysis of the 2-azido-3arylacrylate 5 in an intramolecular cyclisation to form a fused pyrrole skeleton (Scheme 1). The typical solvents that are used are toluene [18], xylenes [28] or mesitylene [38].

Mechanism of the Hemetsberger-Knittel Synthesis
The mechanism [40] of the Hemetsberger-Knittel reaction proceeds via an azirene intermediate 8. The first step is the thermal degradation of 2-azido-3-arylacrylate 5, generating molecular nitrogen and nitrene 7. Nitrene 7 is believed to be in equilibrium with the azirine intermediate 8. The subsequent step is the insertion of the nitrene into the cyclic ring followed by a final [1,5] hydrogen shift that is accompanied by the final re-aromatisation, forming the pyrrole core of the fused aromatic system 1 (Scheme 2).

Scheme 2.
Proposed mechanism of the Hemetsberger-Knittel synthesis of heteropentalenes.

Scheme 2.
Proposed mechanism of the Hemetsberger-Knittel synthesis of heteropentalenes.
The condensation reaction of thiophene-2,5-dicarbaldehyde 19 with ethyl azidoacetate 3 generated compound 20, which was further subjected to cyclisation by heating in toluene to form the thienodipyrrole derivative 21 in an 85% yield (Scheme 6). Compound 21 was used as the starting material for the synthesis of thiophene polymers [45]. Compound 21 can be oxidised with an HOF.CH 3 CN complex to give sulphone 22 with a 95% yield (Scheme 6) [46].
The condensation reaction of thiophene-2,5-dicarbaldehyde 19 with ethyl azidoacetate 3 generated compound 20, which was further subjected to cyclisation by heating in toluene to form the thienodipyrrole derivative 21 in an 85% yield (Scheme 6). Compound 21 was used as the starting material for the synthesis of thiophene polymers [45]. Compound 21 can be oxidised with an HOF.CH3CN complex to give sulphone 22 with a 95% yield (Scheme 6) [46].  Further applications of the Hemetsberger reaction were also reported in the 1990s [47,48]. The intermediate nitrene I was inserted into a п-deficient heterocycle. The versatility of this approach is shown in the synthesis of pyrrolo [3,2-d]thiazoles or selenazoles 24 (Scheme 7). The thermolysis of the 3-thiazolyl-or 3-selenazolyl-2-azidoacrylates 23 produces these bicyclic heterocycles in high yields (85-90%).

Thiazolo [5,4-d]thiazoles
Thiazolo [5,4-d]thiazole (TzTz) is a conjugated (π)-heterocyclic scaffold containing two fused thiazole rings presenting a rigid planar structure (46, Figure 8) [63]. Unsubstituted TzTz is a white powder containing two nitrogen, two sulphur and four carbon atoms, and without a wide range of utilisation, but its derivatives have attracted enormous attention. According to ScienceDirect ® 490 and Scopus ® , 289 peer-reviewed papers/articles on TzTz compounds were published between 1959 and 2021 ( Figure 9). The first papers published by Johnson and Ketcham presented only the preparation of TzTz and provided some other general information, such as UV-Vis spectra, mass spectra and IR characterisation [64]. The number of papers showed a slight increase until 2004, when the first TzTz based donor-acceptor-donor molecules were presented [65,66]. Since 2008, the trend has been for a rapid increase in research works focusing on intensive studies of applications of TzTz in organic electronics. In particular, since the first n-type thiazolo [5,4-d]thiazolebased organic field-effect transistor (OFET) was presented [67], reports on TzTz-containing materials have increased almost exponentially [68]. Although the applications of TzTz-type materials in the development of OFETs [69], organic-light emitting diodes (OLEDs) [70], optical sensors [71] and organic redox flow batteries [72] have already been According to ScienceDirect ® 490 and Scopus ® , 289 peer-reviewed papers/articles on TzTz compounds were published between 1959 and 2021 ( Figure 9). The first papers published by Johnson and Ketcham presented only the preparation of TzTz and provided some other general information, such as UV-Vis spectra, mass spectra and IR characterisation [64]. The number of papers showed a slight increase until 2004, when the first TzTz based donor-acceptor-donor molecules were presented [65,66]. Since 2008, the trend has been for a rapid increase in research works focusing on intensive studies of applications of TzTz in organic electronics. In particular, since the first n-type thiazolo [5,4-d]thiazolebased organic field-effect transistor (OFET) was presented [67], reports on TzTz-containing materials have increased almost exponentially [68]. Although the applications of TzTz-type materials in the development of OFETs [69], organic-light emitting diodes (OLEDs) [70], optical sensors [71] and organic redox flow batteries [72] have already been described, TzTzbased organic photovoltaics (OPVs) [73], including dye-sensitised solar cells (DSSCs) [74], bulk heterojunction solar cells (BHJ) [75], perovskite solar cells [76], hybrid solar cells [77] and polymer solar cells [78] with high values of power conversion efficiency (PCE), ranging from 3% up to a maximum of 17%, have been presented in a vast number of research works. Concerning the structure of the heterocyclic core, the functionalisation of thiazolo [5,4-d]thiazole-based derivatives towards materials with efficient charge transfer, [79] intense absorption and strong fluorescence, [80] as well as higher solubility, is due to the lack of free positions handled mainly through the substituents at C2 and C7 (46, Figure 8) [81].
According to ScienceDirect 490 and Scopus , 289 peer-reviewed papers/articles on TzTz compounds were published between 1959 and 2021 ( Figure 9). The first papers published by Johnson and Ketcham presented only the preparation of TzTz and provided some other general information, such as UV-Vis spectra, mass spectra and IR characterisation [64]. The number of papers showed a slight increase until 2004, when the first TzTz based donor-acceptor-donor molecules were presented [65,66]. Since 2008, the trend has been for a rapid increase in research works focusing on intensive studies of applications of TzTz in organic electronics. In particular, since the first n-type thiazolo [5,4-d]thiazolebased organic field-effect transistor (OFET) was presented [67], reports on TzTz-containing materials have increased almost exponentially [68]. Although the applications of TzTz-type materials in the development of OFETs [69], organic-light emitting diodes (OLEDs) [70], optical sensors [71] and organic redox flow batteries [72] have already been described, TzTz-based organic photovoltaics (OPVs) [73], including dye-sensitised solar cells (DSSCs) [74], bulk heterojunction solar cells (BHJ) [75], perovskite solar cells [76], hybrid solar cells [77] and polymer solar cells [78] with high values of power conversion efficiency (PCE), ranging from 3% up to a maximum of 17%, have been presented in a vast number of research works. Concerning the structure of the heterocyclic core, the functionalisation of thiazolo [5,4-d]thiazole-based derivatives towards materials with efficient charge transfer, [79] intense absorption and strong fluorescence, [80] as well as higher solubility, is due to the lack of free positions handled mainly through the substituents at C2 and C7 (46, Figure 8) [81].

Ketcham's Cyclocondensation Reaction
Pioneering synthesis of TzTz-based compounds was performed by John Johnson and Roger Ketcham, who published their work in 1960. The goal of the authors was to monitor the condensation of dithiooxamide (48) with different aromatic carbaldehydes (47) [64]. A condensation experiment (Scheme 12) was carried out in different solvents (benzyl chloride, phenol, benzene and chloroform) at boiling point temperature. The most commonly used solvents were N,N-dmiethylformamide (DMF), nitrobenzene, chlorbenzene and phenol, or a solvent-free method was applied. The presented TzTz derivatives were formed in moderate to good yields (7-78%). A curiosity concerning the synthesis was that the first condensation between the aromatic aldehyde with rubeanic acid was performed by Ephraim in 1891 [82], but in that period the structure of the products was primarily misstated as 2,2'-diaryl-4,4'-bisthiazetine (49, Scheme 12) [83]. Later, the correct structure of TzTz-based derivatives was confirmed. used solvents were N,N-dmiethylformamide (DMF), nitrobenzene, chlorbenzene and phenol, or a solvent-free method was applied. The presented TzTz derivatives were formed in moderate to good yields (7-78%). A curiosity concerning the synthesis was that the first condensation between the aromatic aldehyde with rubeanic acid was performed by Ephraim in 1891 [82], but in that period the structure of the products was primarily misstated as 2,2'-diaryl-4,4'-bisthiazetine (49, Scheme 12) [83]. Later, the correct structure of TzTz-based derivatives was confirmed. Ketcham cyclocondensation is the most widely utilised process for the synthesis of TzTz-based derivatives, mainly symmetrically substituted by aromatic and heteroaromatic rings (Scheme 12). On the one hand, the reaction represents a very available process since it represents a single step, one-pot method which does not require an inert atmosphere or cooling [84] and can be performed under solvent-free conditions using microwave irradiation [85]. Moreover, dithiooxamide and a broad range of aldehydes are widely affordable at good prices. Still, such an elegant synthetic approach is accompanied by a few drawbacks, such as long reaction times, high reaction temperatures and the formation of products in poor to average yields [86][87][88][89][90]. The formation of by-products, as a consequence of the stepwise process, probably contributes the most to lowering the yield of the desired products.

Mechanism of the Ketcham Reaction
In our previous work [16], we presented the completed mechanism of the Ketcham stepwise process. The proposal was based on our experimental observation, and the structural characterisation of the main products and by-products [16]. Our proposal was supported by data from the literature [91,92], where the authors proposed a shortened version of the mechanism or highlighted the formation of by-products 51 and 54 ( Figure 10) resulting from the process' behaviour. In detail, according to Scheme 13 the condensation of two equivalents of substituted furan-2-carbaldehyde (50) produced the stable iminetype derivative 51. Such iminie-type derivatives are formed during the early stage of the reaction that is followed by a ring-closing reaction, producing the non-isolable dihydro intermediate 52. The process is completed by double intramolecular rearrangement of the dihydro intermediates 52, 53, ending up with oxidative cyclisation to furan-substituted TzTz 55. Some improvements to the oxidation step were presented by the use of SeO2 as Scheme 12.
Ketcham cyclocondensation is the most widely utilised process for the synthesis of TzTz-based derivatives, mainly symmetrically substituted by aromatic and heteroaromatic rings (Scheme 12). On the one hand, the reaction represents a very available process since it represents a single step, one-pot method which does not require an inert atmosphere or cooling [84] and can be performed under solvent-free conditions using microwave irradiation [85]. Moreover, dithiooxamide and a broad range of aldehydes are widely affordable at good prices. Still, such an elegant synthetic approach is accompanied by a few drawbacks, such as long reaction times, high reaction temperatures and the formation of products in poor to average yields [86][87][88][89][90]. The formation of by-products, as a consequence of the stepwise process, probably contributes the most to lowering the yield of the desired products.

Mechanism of the Ketcham Reaction
In our previous work [16], we presented the completed mechanism of the Ketcham stepwise process. The proposal was based on our experimental observation, and the structural characterisation of the main products and by-products [16]. Our proposal was supported by data from the literature [91,92], where the authors proposed a shortened version of the mechanism or highlighted the formation of by-products 51 and 54 ( Figure 10) resulting from the process' behaviour. In detail, according to Scheme 13 the condensation of two equivalents of substituted furan-2-carbaldehyde (50) produced the stable iminetype derivative 51. Such iminie-type derivatives are formed during the early stage of the reaction that is followed by a ring-closing reaction, producing the non-isolable dihydro intermediate 52. The process is completed by double intramolecular rearrangement of the dihydro intermediates 52, 53, ending up with oxidative cyclisation to furan-substituted TzTz 55. Some improvements to the oxidation step were presented by the use of SeO 2 as an oxidising agent [93]. This approach shows oxidation from the cyclised 2,3-dihydrothiazolo [5,4-d]thiazole (Scheme 13, Pathway B). The free amino group of the initially formed single thiazole ring allows condensation with another amount of aldehyde. The intermediate bearing the -SH moiety, possibly dimerize, forms the bisthiol-type compound 54 in which the S-S bond is subsequently cleaved. The unsaturated TzTz core is oxidised further. In spite of that, the presented proceeding could be taken as being hypothetical, according to two independent research works previously published in [16,93]. It has to be mentioned that the formation, isolation and identification of intermediate bis-thiol type derivative 54 ( Figure 10) was possible only if the presence of the oxygen atom of the substituent stabilised the nitrogen of the imine bond by intramolecular effects. Such a phenomenon, nevertheless, has not been discussed as of yet.
Reactions 2023, 4, FOR PEER REVIEW 13 Scheme 13. Proposed mechanism of the Ketcham reaction according to [16,[91][92][93], including the formation of imines 51 as isolable and stable types of by-products (Pathway A) and  Figure 10. Chemical structure of Ketcham's reaction by-products-the common imine-type derivative 51 and unusual bis-thiol type 54, evidenced only twice according to [16,93]. The possible intramolecular effects are proposed-the dipole-dipole interactions (red arrow) and hydrogen bonds (red dashed line) as a probable interpretation of the stabilisation of this unusual by-product.

Synthesis of Asymmetrical thiazolo [5,4-d]thiazoles by Ketcham's Reaction
It is quite surprising to achieve an asymmetrically substituted TzTz-based compound through simple cyclocondensation. To the best of our knowledge, there have only been two examples of such phenomenon in the literature presented until now.
The first example was presented in the literature very recently, in 2022, and it shows the use of two different carbaldehydes, pyrene-1-carbaldehyde 55 and 4-pyridinecarboxaldehyde 56, in a ratio of 1:1 in cyclocondensation with dithiooxamide (48) towards C2pyrene and C7 p-pyridine-substituted thiazolo [5,4-d]thiazole 57 (Scheme 14) [94]. Interestingly, the authors report only the sole asymmetric product; however, the character of this reaction would possibly enable the formation of symmetrical products as well. Another example of the achievement of asymmetrical TzTz derivative 56 using a direct Ketcham procedure was presented recently [95]. The reaction of ferrocenyl aldehyde (58) with protochatecuic aldehyde (59) produced thiazolo [5,4-d] [95]. Figure 10. Chemical structure of Ketcham's reaction by-products-the common imine-type derivative 51 and unusual bis-thiol type 54, evidenced only twice according to [16,93]. The possible intramolecular effects are proposed-the dipole-dipole interactions (red arrow) and hydrogen bonds (red dashed line) as a probable interpretation of the stabilisation of this unusual by-product.
Reactions 2023, 4, FOR PEER REVIEW 12 an oxidising agent [93]. This approach shows oxidation from the cyclised 2,3-dihydrothiazolo [5,4-d]thiazole (Scheme 13, Pathway B). The free amino group of the initially formed single thiazole ring allows condensation with another amount of aldehyde. The intermediate bearing the -SH moiety, possibly dimerize, forms the bisthiol-type compound 54 in which the S-S bond is subsequently cleaved. The unsaturated TzTz core is oxidised further. In spite of that, the presented proceeding could be taken as being hypothetical, according to two independent research works previously published in [16,93]. It has to be mentioned that the formation, isolation and identification of intermediate bis-thiol type derivative 54 ( Figure 10) was possible only if the presence of the oxygen atom of the substituent stabilised the nitrogen of the imine bond by intramolecular effects. Such a phenomenon, nevertheless, has not been discussed as of yet.

Synthesis of Asymmetrical Thiazolo [5,4-d]thiazoles by Ketcham's Reaction
It is quite surprising to achieve an asymmetrically substituted TzTz-based compound through simple cyclocondensation. To the best of our knowledge, there have only been two examples of such phenomenon in the literature presented until now.
The first example was presented in the literature very recently, in 2022, and it shows the use of two different carbaldehydes, pyrene-1-carbaldehyde 55 and 4-pyridinecarboxaldehyde 56, in a ratio of 1:1 in cyclocondensation with dithiooxamide (48) towards C2-pyrene and C7 p-pyridine-substituted thiazolo [5,4-d]thiazole 57 (Scheme 14) [94]. Interestingly, the authors report only the sole asymmetric product; however, the character of this reaction would possibly enable the formation of symmetrical products as well.  Figure 10. Chemical structure of Ketcham's reaction by-products-the common imine-type derivative 51 and unusual bis-thiol type 54, evidenced only twice according to [16,93]. The possible intramolecular effects are proposed-the dipole-dipole interactions (red arrow) and hydrogen bonds (red dashed line) as a probable interpretation of the stabilisation of this unusual by-product.

Synthesis of Asymmetrical thiazolo [5,4-d]thiazoles by Ketcham's Reaction
It is quite surprising to achieve an asymmetrically substituted TzTz-based compound through simple cyclocondensation. To the best of our knowledge, there have only been two examples of such phenomenon in the literature presented until now.
The first example was presented in the literature very recently, in 2022, and it shows the use of two different carbaldehydes, pyrene-1-carbaldehyde 55 and 4-pyridinecarboxaldehyde 56, in a ratio of 1:1 in cyclocondensation with dithiooxamide (48) towards C2pyrene and C7 p-pyridine-substituted thiazolo [5,4-d]thiazole 57 (Scheme 14) [94]. Interestingly, the authors report only the sole asymmetric product; however, the character of this reaction would possibly enable the formation of symmetrical products as well. Another example of the achievement of asymmetrical TzTz derivative 56 using a direct Ketcham procedure was presented recently [95]. The reaction of ferrocenyl aldehyde (58) with protochatecuic aldehyde (59) produced thiazolo [5,4- Another example of the achievement of asymmetrical TzTz derivative 56 using a direct Ketcham procedure was presented recently [95]. The reaction of ferrocenyl aldehyde (58) with protochatecuic aldehyde (59) produced thiazolo [5,4- Figure 10. Chemical structure of Ketcham's reaction by-products-the common imine-type derivative 51 and unusual bis-thiol type 54, evidenced only twice according to [16,93]. The possible intramolecular effects are proposed-the dipole-dipole interactions (red arrow) and hydrogen bonds (red dashed line) as a probable interpretation of the stabilisation of this unusual by-product.

Synthesis of Asymmetrical thiazolo [5,4-d]thiazoles by Ketcham's Reaction
It is quite surprising to achieve an asymmetrically substituted TzTz-based compound through simple cyclocondensation. To the best of our knowledge, there have only been two examples of such phenomenon in the literature presented until now.
The first example was presented in the literature very recently, in 2022, and it shows the use of two different carbaldehydes, pyrene-1-carbaldehyde 55 and 4-pyridinecarboxaldehyde 56, in a ratio of 1:1 in cyclocondensation with dithiooxamide (48) towards C2pyrene and C7 p-pyridine-substituted thiazolo [5,4-d]thiazole 57 (Scheme 14) [94]. Interestingly, the authors report only the sole asymmetric product; however, the character of this reaction would possibly enable the formation of symmetrical products as well. Another example of the achievement of asymmetrical TzTz derivative 56 using a direct Ketcham procedure was presented recently [95]. The reaction of ferrocenyl aldehyde (58) with protochatecuic aldehyde (59) produced thiazolo [5,4-

Cyclopolymerisations Following Ketcham's Reaction Protocol
Recently, a very promising way to achieve a TzTz-based oligomer or polymer directly was offered by the simple Ketcham's synthetic protocol. Instead of a small-molecule thiazolo [5,4-d]thiazole-type derivative, the compound had approximately two to seven repeating TzTz units in the final oligo-or polymer. Such types of reactions are rather rare, but this seems to be very promising for the construction of organic materials with enhanced π-conjugation and the required electronic properties. Reports on Ketcham-type polycondensation have recently garnered interest. At the moment, there are on average only ten reports [96][97][98][99][100][101][102][103][104][105] presenting the direct Ketcham reaction approach towards TzTz-based oligomers and polymers. 1.
The first report, published in 2016 [96], presented the synthesis of a 9-hexyl-9H-carbazoleunit bearing a TzTz-based oligomer 61 with seven repeating units (Figure 11a). A similar product geared towards the same oligomer was presented in 2021 [97].

2.
The polycondensation reaction of the Ketcham-type of dithiooxamide with triethylamine and carbazole-based aldehydes was published by Dabuliene at al. in 2022 [98]. GPC analysis showed the average molecular weights of triphenylamine-based compounds (62) (Figure 11b) [99] demonstrated the preparation of a porous cross-linked polymer 64 (Figure 11c) containing TzTz and phenyl units. Similar phenyl-based monomers with three carbaldehyde groups, such as tris(4-formylphenyl)-benzene and tetra(4formylphenyl)-benzene, can be also condensed with dithiooxamide to give a crosslinked copolymer with a porous structure [100]. 4.
Finally, the structure of cross-linked polymers 67 as products of Ketcham's type polycondensation of dithiooxamide with different monomers containing multiple carbaldehyde groups was described according to [104] (Figure 11f). 7.
The polycondensation approach following the Ketcham procedure was successfully used to achieve porous, cross-linked copolymer containing porphyrin-residues 68 (Scheme 16) [105].

Conclusions
In combination with our several years of experience in the field of synthesis and applications of furo [3,2-b]pyrroles and thiazolo [5,4-d]thiazole-based derivatives with respect to published research work, the knowledge and current "state-of-the-art" of the Hemetsberger-Knittel synthesis regarding furopyrroles and their sulphur-and selenoheteroatom containing derivatives and the Ketcham cyclocondensation methodology affording thiazolothiazoles is detailed herein. The primary interest is focused on the preparation processes, benefits and drawback of each method. The mechanism or the proposal of the mechanism is discussed. Both types of discussed heteropentalenes are very important in applied sciences. Furo [3,2-b]pyrroles exhibit a variety of pharmacological effects, and thiazolo [5,4-d]thiazole are targets of materials research, particularly in the field of optoelectronic materials. Both the Hemetsberger-Knittel approach and the Ketcham synthesis represent a versatile route towards a concrete type of heteropentalenes. Under current review are insights into both methodologies with the ambition of the further design and synthesis of a novel type of heteropentalenes with two (1:1); three (1:2)/(2:1) and four (2:2) mainly O, S,N heteroatoms. Both series of compounds are of prospective interest for pharmacological sciences (furopyrroles) and for materials research (thiazolothiazoles). Current applications of thieno-, selenopheno, pyrrolo [3,2-b]pyrroles are included as well, mainly focusing on fields of materials chemistry.

Conflicts of Interest:
The authors declare no conflicts of interest. Scheme 16. Synthesis of porphyrin-centred TzTz-based copolymer achieved by simple Ketcham's synthetic protocol according to [105].
With the final example presented in Scheme 16, it can be concluded that the utilisation of Ketcham's ring-closure method significantly extends beyond its generally accepted potential. The polycyclocondensation approach is, moreover, a novel alternative way to achieve novel functional materials using a simple, one-step manner affecting significant cost-reduction and enhancement of the eco-friendliness of the entire process, from design through synthesis up to real-life application.

Conclusions
In combination with our several years of experience in the field of synthesis and applications of furo [3,2-b]pyrroles and thiazolo [5,4-d]thiazole-based derivatives with respect to published research work, the knowledge and current "state-of-the-art" of the Hemetsberger-Knittel synthesis regarding furopyrroles and their sulphur-and seleno-heteroatom containing derivatives and the Ketcham cyclocondensation methodology affording thiazolothiazoles is detailed herein. The primary interest is focused on the preparation processes, benefits and drawback of each method. The mechanism or the proposal of the mechanism is discussed. Both types of discussed heteropentalenes are very important in applied sciences. Furo [3,2-b]pyrroles exhibit a variety of pharmacological effects, and thiazolo [5,4-d]thiazole are targets of materials research, particularly in the field of optoelectronic materials. Both the Hemetsberger-Knittel approach and the Ketcham synthesis represent a versatile route towards a concrete type of heteropentalenes. Under current review are insights into both methodologies with the ambition of the further design and synthesis of a novel type of heteropentalenes with two (1:1); three (1:2)/(2:1) and four (2:2) mainly O, S,N heteroatoms. Both series of compounds are of prospective interest for pharmacological sciences (furopyrroles) and for materials research (thiazolothiazoles). Current applications of thieno-, selenopheno, pyrrolo [3,2-b]pyrroles are included as well, mainly focusing on fields of materials chemistry.