Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination–Cyclization Reaction between Simple Alkynes and Arylhydrazines

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C–C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.


Introduction
The vast number of interesting biologically active indole-containing systems in both natural products and pharmaceutically relevant compounds [1][2][3] is the main reason for the ongoing attention to developing de novo synthesis of these molecules [4].Among the constellation of methodologies known today [5][6][7][8][9], the classic Fischer indole synthesis (Scheme 1a), as well as its modern variants [4,[10][11][12], continue to represent valuable and effective approaches for accessing a wide range of these heterocyclic scaffolds [13,14].One subclass among this type of reaction is based on the transition metal-catalyzed hydroamination [15,16] of alkynes with various nitrogen sources [17][18][19], including arylhydrazines.Although in the latter case (Scheme 1b), it does not eliminate the primary difficulty associated with the Fischer indole synthesis such as the limited commercial availability of the hydrazine substrates, alkynes themselves are generally readily accessible and inexpensive starting materials.Thereby, their use imposes an additional level of synthetic practicality to those Fisher-type reactions and constitutes a valuable alternative route to the indole scaffold.In turn, we would like to report here the first, to our knowledge, example of a metal-free, Bronsted acid-mediated hydroamination of alkynes with arylhydrazines, which, when followed by a one-pot Fisher-type cyclization, results in a variety of indoles in good to excellent yields (Scheme 2j).phosphoric (entry 8) or 80% polyphosphoric (entry 9) acids in the presence of co-solvents (ethanol and toluene, respectively) is also possible; although, if in the case of the former (entry 8), a noticeable deterioration of the reaction mixture and significant drop in yield (33%) were observed.
Table 1.Screening of reaction parameters for the synthesis of the 2-phenylindole 3aa.[56].In addition, PPA being a moderately strong, non-oxidizing acid, capable of dissolving organic compounds and having powerful dehydrating properties, is well known as an effective reagent, catalyst, or reaction medium for numerous synthetic applications [57,58].Being both commercially available and readily prepared [58,59] in-house (by dissolving calculated amounts of P2O5 in 85% orthophosphoric acid), PPA is generally used either as an emulsion in inert high-boiling solvents (xylenes, toluene, etc.) [40,60], silica gel-supported [61] reagent, or as a reaction medium [58], typically in a 10-50-fold excess (by weight).
Therefore, we decided to use the reaction of phenylhydrazine 1a with phenylacetylene 2a in the presence of PPA as a model one.The results of these screening experiments are given in Table 1.It should be noted that the main difference between 80 and 87% PPA is its composition [57].The former consists mainly of ortho-, pyro-, tri-, and tetraphosphoric acids (n = 1-4), while "strong" PPA (above 86 w.t.% of P 2 O 5 ) is composed largely of high molecular weight, linear as well as cyclic, polymeric (n > 7) species.In our experience, it is hard to say at the outset which type of PPA will perform better in a particular reaction, so as a rule, it is necessary to test both options.And since the precise composition of polyphosphoric acid and the detailed mechanism of transformation catalyzed by PPA are usually unknown, only speculative assumptions can be made about the role of PPA concentration in any given reaction.
However, an intriguing aspect was the possibility of running this reaction as an emulsion in toluene (entry 9).The latter means that the indole synthesis described herein can be conducted without the need for aqueous post-treatment and be easily scaled up.Thus, according to the leading reported work [40], using toluene as a cosolvent and only a 3-fold excess (not 10!) of PPA (w/w), up to 3 kg of indole derivatives were prepared in one batch via the classical Fisher reaction between ketones and arylhydrazines.The key factor here is the precipitation of PPA at the bottom of the reactor after the reaction is complete.The authors then simply separate the upper toluene layer and remove solvent under reduced pressure, obtaining the target products in high yields (up to 99%) and purity (>95%).We believe that the same methodology can be applied to our conceptually very similar PPA-assisted reaction between alkynes and arylhydrazines.
At this point, with the working conditions in hand, we were ready to assemble a small library of indoles 3 (Scheme 3).In terms of scope and general applicability, the results obtained are rather similar to those we observed previously in the PPA-assisted Fisher indole synthesis by the reaction of arylhydrazines with acetophenones [62].The benchmark, unsubstituted phenylhydrazine 2a, gives the target indole 3aa in an excellent yield of 93%.In turn, the introduction of donor alkyl substituents as in 2b-e or the use of arylhydrazines 2f-i bearing the electron-withdrawing groups did not have a significant effect on the overall outcome of the process, providing yields of 69-81%.Regarding acetylenes, the terminal (2-naphthyl)acetylene 1b gave the corresponding indole 3ba in a respectable 81% yield, while the internal alkyne 1c performed a bit worse (61% of 3ca).However, such inner alkynes are much more accessible [63] than the corresponding arylbenzyl ketones, which is a significant advantage.
ketones, which is a significant advantage.
Also, in our experience the substrate/PPA ratio of 1 to 10 by weight is not something immutable, and sometimes the amount of polyphosphoric acid could be significantly reduced (up to 3 times, for example, as in the case of 2-naphthylindole 3ba), as long as the viscosity of the reaction mixture both at the beginning and at the end of the reaction, when ammonium phosphates accumulate, allows for proper stirring.Plausible mechanisms for this cascade transformation are presented in Scheme 4. The first possible pathway is associated with the direct nucleophilic attack of hydrazine 2 on vinyl cation 4 generated from acetylenes 1 in PPA (Scheme 4a).The resulting enhydrazine 5 obviously undergoes the classical Fischer reaction under the reaction conditions.
Another feasible route (Scheme 4b) suggests that ketone 7 could be formed directly under anhydrous conditions by acidolysis of vinyl phosphate intermediate 6 in a manner similar to how carboxylic acids and vinyl acetates react in the presence of an acid catalyst to form mixed anhydrides and ketones [64,65].However, no special attempts have been made to distinguish between these two possible routes or to isolate or observe the intermediate vinyl phosphates.Also, in our experience the substrate/PPA ratio of 1 to 10 by weight is not something immutable, and sometimes the amount of polyphosphoric acid could be significantly reduced (up to 3 times, for example, as in the case of 2-naphthylindole 3ba), as long as the viscosity of the reaction mixture both at the beginning and at the end of the reaction, when ammonium phosphates accumulate, allows for proper stirring.
Plausible mechanisms for this cascade transformation are presented in Scheme 4. The first possible pathway is associated with the direct nucleophilic attack of hydrazine 2 on vinyl cation 4 generated from acetylenes 1 in PPA (Scheme 4a).The resulting enhydrazine 5 obviously undergoes the classical Fischer reaction under the reaction conditions.To further evaluate the possible mechanism of the discussed PPA-assisted tandem synthesis of indoles, blank experiments were carried out with phenylacetylene 1a alone as a model substrate under the same conditions (Table 2).Another feasible route (Scheme 4b) suggests that ketone 7 could be formed directly under anhydrous conditions by acidolysis of vinyl phosphate intermediate 6 in a manner similar to how carboxylic acids and vinyl acetates react in the presence of an acid catalyst to form mixed anhydrides and ketones [64,65].However, no special attempts have been made to distinguish between these two possible routes or to isolate or observe the intermediate vinyl phosphates.
To further evaluate the possible mechanism of the discussed PPA-assisted tandem synthesis of indoles, blank experiments were carried out with phenylacetylene 1a alone as a model substrate under the same conditions (Table 2).To further evaluate the possible mechanism of the discussed PPA-assisted tandem synthesis of indoles, blank experiments were carried out with phenylacetylene 1a alone as a model substrate under the same conditions (Table 2).The obtained results correlate well with those of the indole synthesis (Table 1).In each case, after aqueous workup, the corresponding acetophenone 7a was usually formed in good to excellent yields.Although polyphosphoric acid (PPA 80%) was still found to be the most suitable in terms of yields (entries 1-5), this time we did not observe any changes at different acid-to-substrate ratios.This is most likely due to the absence of ammonia, which is released during the Fisher synthesis and acts as an acid trap.Finally, the rate of hydrolysis we observed was significantly lower than the rate of the tandem hydroamination-indolization reaction (1.5 vs. 0.5 h) discussed above, suggesting that the latter occurs presumably through the direct attack of hydrazine on the acetylene moiety (Scheme 4a) rather than the formation of ketone product 7 first (Scheme 4b).
To demonstrate the general applicability of this protocol, a set of 11 acetophenones 7, including 3 new ones (7f,k,l), were prepared (Scheme 5).Overall, the reaction proceeded smoothly with slight differences in yields depending on the structure of the starting acetylenes.Thus, both simple donor-and acceptor-substituted phenylacetylenes 1a,hj provide equally high yields of the corresponding acetophenones 7a,h-j.The synthesis of ketones like 7d and 7e may be particularly useful here, since the standard approach to such compounds involves the alkylation of the benzimidazole or phthalimide derivatives with the corresponding, usually highly lacrimal α-haloketones.Another example of a synthetically valuable approach is the PPA-assisted hydrolysis of the Sonogashira adduct 1f, which results in the corresponding arylheteroaryl ketone 7f. a All reactions were performed on 1 mmol scales.Isolated yields of purified materials are provided.
The obtained results correlate well with those of the indole synthesis (Table 1).In each case, after aqueous workup, the corresponding acetophenone 7a was usually formed in good to excellent yields.Although polyphosphoric acid (PPA 80%) was still found to be the most suitable in terms of yields (entries 1-5), this time we did not observe any changes at different acid-to-substrate ratios.This is most likely due to the absence of ammonia, which is released during the Fisher synthesis and acts as an acid trap.Finally, the rate of hydrolysis we observed was significantly lower than the rate of the tandem hydroamination-indolization reaction (1.5 vs. 0.5 h) discussed above, suggesting that the latter occurs presumably through the direct attack of hydrazine on the acetylene moiety (Scheme 4a) rather than the formation of ketone product 7 first (Scheme 4b).
To demonstrate the general applicability of this protocol, a set of 11 acetophenones 7, including 3 new ones (7f,k,l), were prepared (Scheme 5).Overall, the reaction proceeded smoothly with slight differences in yields depending on the structure of the starting acetylenes.Thus, both simple donor-and acceptor-substituted phenylacetylenes 1a,h-j provide equally high yields of the corresponding acetophenones 7a,h-j.The synthesis of ketones like 7d and 7e may be particularly useful here, since the standard approach to such compounds involves the alkylation of the benzimidazole or phthalimide derivatives with the corresponding, usually highly lacrimal α-haloketones.Another example of a synthetically valuable approach is the PPA-assisted hydrolysis of the Sonogashira adduct 1f, which results in the corresponding arylheteroaryl ketone 7f.
Overall, we think that although the synthesis of simple ketones is generally not a particularly challenging task, and many excellent methods exist to accomplish it, including the classical Kucherov reaction [66,67], the given procedure will be a valuable addition to the current arsenal of proven synthetic protocols.
The plausible reaction mechanism is shown in Scheme 6.As PPA is known for its strong dehydrating properties, it seems unlikely that this reaction proceeds through the classical Lewis/Bronsted acid-catalyzed alkyne hydration pathway also referred to as the Kucherov reaction [66,67].Arguably, it involves the protonation of acetylene 1, followed by the attack of phosphoric acid on the vinyl cation 4.After treatment with water, the vinyl phosphate 6 is released in the form of the corresponding enol 8, which then quickly tautomerizes to ketone 7.
Overall, we think that although the synthesis of simple ketones is generally not a particularly challenging task, and many excellent methods exist to accomplish it, including the classical Kucherov reaction [66,67], the given procedure will be a valuable addition to the current arsenal of proven synthetic protocols.The plausible reaction mechanism is shown in Scheme 6.As PPA is known for its strong dehydrating properties, it seems unlikely that this reaction proceeds through the classical Lewis/Bronsted acid-catalyzed alkyne hydration pathway also referred to as the Kucherov reaction [66,67].Arguably, it involves the protonation of acetylene 1, followed by the attack of phosphoric acid on the vinyl cation 4.After treatment with water, the vinyl phosphate 6 is released in the form of the corresponding enol 8, which then quickly tautomerizes to ketone 7. Scheme 6. Probable mechanism of PPA-assisted conversion of alkynes 1 into ketones 7.

General Information
NMR spectra, 1 H, and 13 C were measured in solutions of CDCl3 or DMSO-d6 on a Bruker AVANCE-III HD instrument (at 400 and 101 MHz, respectively).Residual solvent signals were used as internal standards, in DMSO-d6 (2.50 ppm for 1 H, and 40.45 ppm for 13 С nuclei) or CDCl3 (7.26 ppm for 1 H, and 77.16 ppm for 13 С nuclei).HRMS spectra were measured on a Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO2Na-HCO2H for calibration).IR spectra were measured on a FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module.See Supplementary Materials for the NMR (Figures S1-S46) and HRMS (Figures S47-S53) spectral charts.Reaction progress, purity of isolated compounds, and Rf values were monitored with TLC on Silufol UV-254 plates.Column chromatography was performed on silica gel (32-63 μm, 60 Å pore size).Melting points were measured with the Stuart SMP30 apparatus.The plausible reaction mechanism is shown in Scheme 6.As PPA is known for its strong dehydrating properties, it seems unlikely that this reaction proceeds through the classical Lewis/Bronsted acid-catalyzed alkyne hydration pathway also referred to as the Kucherov reaction [66,67].Arguably, it involves the protonation of acetylene 1, followed by the attack of phosphoric acid on the vinyl cation 4.After treatment with water, the vinyl phosphate 6 is released in the form of the corresponding enol 8, which then quickly tautomerizes to ketone 7. Scheme 6. Probable mechanism of PPA-assisted conversion of alkynes 1 into ketones 7.

General Information
NMR spectra, 1 H, and 13 C were measured in solutions of CDCl3 or DMSO-d6 on a Bruker AVANCE-III HD instrument (at 400 and 101 MHz, respectively).Residual solvent signals were used as internal standards, in DMSO-d6 (2.50 ppm for 1 H, and 40.45 ppm for 13 С nuclei) or CDCl3 (7.26 ppm for 1 H, and 77.16 ppm for 13 С nuclei).HRMS spectra were measured on a Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO2Na-HCO2H for calibration).IR spectra were measured on a FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module.See Supplementary Materials for the NMR (Figures S1-S46) and HRMS (Figures S47-S53) spectral charts.Reaction progress, purity of isolated compounds, and Rf values were monitored with TLC on Silufol UV-254 plates.Column chromatography was performed on silica gel (32-63 μm, 60 Å pore size).Melting points were measured with the Stuart SMP30 apparatus.Scheme 6. Probable mechanism of PPA-assisted conversion of alkynes 1 into ketones 7.

General Information
NMR spectra, 1 H, and 13 C were measured in solutions of CDCl 3 or DMSO-d 6 on a Bruker AVANCE-III HD instrument (at 400 and 101 MHz, respectively).Residual solvent signals were used as internal standards, in DMSO-d 6 (2.50 ppm for 1 H, and 40.45 ppm for 13 C nuclei) or CDCl 3 (7.26ppm for 1 H, and 77.16 ppm for 13 C nuclei).HRMS spectra were measured on a Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO 2 Na-HCO 2 H for calibration).IR spectra were measured on a FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module.See Supplementary Materials for the NMR (Figures S1-S46) and HRMS (Figures S47-S53) spectral charts.Reaction progress, purity of isolated compounds, and R f values were monitored with TLC on Silufol UV-254 plates.Column chromatography was performed on silica gel (32-63 µm, 60 Å pore size).Melting points were measured with the Stuart SMP30 apparatus.Acetylenes 1d [68], 1e [69], and 1f [70] were synthesized according to the previously reported procedures and were identical to those described.All other reagents and solvents were purchased from commercial vendors and used as received.

Preparation of Indoles 3 (General Procedure)
A 5 mL round-bottom flask equipped with a magnetic stir bar was charged with acetylene 1 (1.00 mmol), arylhydrazine 2 (1.00 mmol) (or its hydrochloride), and polyphosphoric acid (2 g, P 2 O 5 80 w.t.%) and stirred upon heating at 100 • C for 30 min (TLC control).After the reaction was complete, the mixture was poured into 80 mL of cold water and basified with 20% ammonia solution.After extraction with EtOAc (4 × 20 mL), the organic fraction was concentrated in vacuo, and the crude material was purified by column chromatography (EtOAc/Hexane).

Preparation of Acetophenones 7 (General Procedure)
A 5 mL round-bottom flask equipped with a magnetic stir bar was charged with acetylene 1 (1.00 mmol) and polyphosphoric acid (2 g, P 2 O 5 80 w.t.%) and stirred upon heating at 100 • C for 30 min (TLC control).After the reaction was complete, the mixture was poured into 80 mL of cold water and basified with 20% ammonia solution.After extraction with EtOAc (4 × 20 mL), the organic fraction was concentrated in vacuo, and the crude material was purified by column chromatography (EtOAc/Hexane).

Scheme 3 .
Scheme 3. A set of indoles 3 prepared by the reaction between acetylenes 1 and arylhydrazines 2.

Scheme 3 .
Scheme 3. A set of indoles 3 prepared by the reaction between acetylenes 1 and arylhydrazines 2.

Scheme 4 .
Scheme 4. Plausible mechanisms for the formation of indoles 3.

Table 1 .
Screening of reaction parameters for the synthesis of the 2-phenylindole 3aa.
a All reactions were performed on 1 mmol scales and equimolar quantities of reactants.Isolated yields of purified materials are provided.

Table 2 .
Screening of reaction parameters for PPA-assisted hydrolysis of phenylacetylene 1a.

Table 2 .
Screening of reaction parameters for PPA-assisted hydrolysis of phenylacetylene 1a.
a All reactions were performed on 1 mmol scales.Isolated yields of purified materials are provided.