The Pschorr Reaction: Recent Advances and Application in Heterocyclic Synthesis

Abstract

The Pschorr reaction is a radical-mediated intramolecular cyclization involving diazonium salts, affording five-, six- and seven-membered fused polycyclic and heterocyclic rings, discovered by R. Pschorr in the late nineteenth century. Over the years, this classic reaction has played an important role in ring-forming reactions. In 2009 we reviewed the progress in the field. The intervening years have witnessed major advances in the application of Pschorr reaction that are mediated by various metals, by photocatalysis, and by ionic liquids, leading to the development of new and improved methods for the synthesis of diverse bioactive heterocycles. The notable progress in the field since our 2009 review provided the impetus to summarize, discuss, and put these advances in perspective.

1. Introduction

The Pschorr reaction [1], along with the Sandmeyer [2], Gomberg–Gatterman [3], Balz–Schiemann [4], and Meerwein [5] reactions, forms a classical dynamic quintet for the introduction of aryl groups, by forming aryl radicals or aryl cations via homolytic or heterolytic dediazoniation, starting from aryldiazonium salts. Collectively, these reactions have had a tremendous impact on synthetic/preparative organic chemistry for the preparation of high-value chemicals, as well as the synthesis of polycyclic aromatic hydrocarbons (PAHs) and hetero-PAHs. As a radical-mediated intramolecular cyclization process, the Pschorr reaction stands out as a classic method for the synthesis of five-, six- and seven-membered fused polycylic and heterocyclic rings. The common link in all of these “name reactions” is the formation of aryl electrophiles from aryldiazonium salts.

The last two decades have witnessed a revival of interest in diazonium chemistry [6,7,8,9,10]. In connection to our long-standing interest in the mechanistic and synthetic aspects of dediazoniation and diazonium ion chemistry [11,12,13,14,15,16,17], and in view of the recent advances that have led to the development of newer methods for the synthesis of diverse bioactive heterocycles, herein we summarize and discuss the progress in this area during the past 15 years.

2. Metal-Redox-Catalyzed Pschorr Reaction

2.1. Palladium-Catalyzed Pschorr Reaction

Synthesis of Benzochromenes

The benzochromene moiety is present in diverse natural products and bioactive molecules [18]. A Pd-catalyzed Pschorr reaction provided facile access to 6H-benzo[c]chromene derivatives 8 and 9 (

Table 1. Synthesis of 6H-benzo[c]chromenes 8 via a Pd(OAc)₂-catalyzed Pschorr reaction from diazonium salts 4.

Entry	Compound	R	R2	Yield (%)
1	8a	H	H	75
2	8b	Br	H	68
3	8c	Cl	H	70
4	8d	Me	H	76
5	8e	H	Me	75
6	8f	Me	Me	80
7	8g	Cl	Me	72
8	8h	Br	Me	71
9	8i	H	tBu	78
10	8j	Me	tBu	83
11	8k	Cl	tBu	76
12	8l	Br	tBu	72
13	8m	OMe	H	48
14	8n	H	CO2Et	83

and

Table 2. Synthesis of 6H-benzo[c]chromenes 9 via a Pd(OAc)₂-catalyzed Pschorr reaction from diazonium salts 7.

Entry	Compound	R2	Yield (%)
1	9a	H	65
2	9b	4-F	52
3	9c	4-Cl	50
4	9d	4-Br	68
5	9e	4-Me	58
6	9f	2-Me	57

) by intramolecular cyclization of o-diazonium tetrafluoroborates 4 and 7, respectively [19]. The key diazonium precursors 4 and 7 were obtained from a two-step sequence starting from benzyl halides 1, via etherification, reduction, and diazotization according to Scheme 1.

Subsequent treatment of the diazonium salts 4 with Pd(OAc)₂ and K₂CO₃ under reflux in ACN afforded the corresponding 6H-benzo[c]chromenes 8 (Table 1).

Optimization studies showed that Pd(OAc)₂ was superior to Pd(PPh₃)₄ and Pd(ACN)₂Cl₂, as these catalysts gave lower yields. Screening of solvents showed that ACN was an optimal solvent, as DMF, EtOH and acetone gave lower yields, and for the base employed, K₂CO₃ proved superior to Na₂CO₃, Cs₂CO₃, TEA or to no base. Treatment of the diazonium salts 7 under the established conditions afforded the respective 6H-benzo[c]chromenes 9 (Table 2).

The method exhibited wide functional group tolerance (i.e., Cl, Br, OMe, tBu, etc.) and substitution patterns, starting from precursors 1, 2 and 5.

The suggested mechanism for the intramolecular cyclization of the diazonium salt 4a (R,R² = H) (Scheme 2) involves reduction of Pd(II) to Pd(0), formation of species A by oxidative addition with release of N₂, intramolecular C–H insertion of Pd to form the tricyclic species B, and reductive elimination to give 8a.

2.2. Copper-Catalyzed Pschorr Reaction

2.2.1. Total Synthesis of the 4,5-Didehydroguadiscine 18a

This compound belongs to a diverse family of isoquinoline alkaloids, an aporphinoid with potent melanogenesis-inhibitory activity. The synthetic sequence of 18a incorporated a Pschorr cyclization on a benzylisoquinoline intermediate (Scheme 3) [20]. The nitrophenylpropanoic acid 10 was converted to acyl chloride 11 by treatment with SOCl₂ which was then coupled with piperonylamine 12 using Carpino’s peptide coupling method [21], to form the amide intermediate 13. An intramolecular POCl₃-mediated cyclization of 13 generated the isoquinoline nucleus 14, which upon dehydrogenation with MnO₂ furnished the aromatic isoquinoline 15. Selective reduction of the nitro group using zinc in acidic medium produced the aniline 16, which was treated with NaNO₂/H₂SO₄, affording the corresponding diazonium salt 17. Finally, the Pschorr reaction was accomplished by treatment of the diazonium salt 17 with CuCl under methanol-free conditions, promoting the intramolecular radical cyclization, leading to the formation of the expected tetracyclic 4,5-didehydroguadiscine framework 18a (R = OMe) (Scheme 3).

In the presence of MeOH, a competing single-electron reduction pathway of the diazonium intermediate 17 occurred, generating the side-product 19. This finding highlights the influence of the solvent on the regioselectivity of the process. Pharmacological assays indicated that compound 18a has significant melanogenesis inhibition (IC₅₀ = 4.7 μM), making it approximately 40 times more potent than arbutin (IC₅₀ = 174 μM), the reference drug, positioning compound 18a as the most active natural inhibitor within this family of compounds.

2.2.2. Synthesis of Diversely Substituted 4,5-Didehydroguadiscines 18

As mentioned before, the 4,5-didehydroguadiscine 18a (R,R¹ = OCH₂O; R² = OMe) (Scheme 4) is a naturally occurring alkaloid with remarkable melanogenesis-inhibitory activity. It features an aporphine scaffold with an aromatized B-ring, a structural motif that has received limited attention in structure–activity relationship (SAR) studies [22,23]. In this context, a further approach for the synthesis of a series of 4,5-didehydroguadiscine derivatives 18 was reported (Scheme 4) [24]. The synthetic route involves coupling of nitrocarboxylic acids 10 and phenethylamines 12 in the presence of EDC·HCl, AtOH, and a proton sponge (PS) to afford amides 13. Subsequently, the Bischler–Napieralski cyclization of amides 13 in toluene afforded the corresponding dihydroisoquinoline derivatives 14. For amides 13 lacking activating substituents, derivatives 14 could still be obtained by using ACN as solvent albeit in lower yields. The dihydroisoquinolines 14 were efficiently converted into the corresponding nitro-isoquinolines 15 by a MnO₂-mediated oxidative dehydrogenation reaction. The resulting nitro-substituted intermediates 15 were then reduced by treatment with zinc dust in the presence of NH₄Cl to furnish aniline derivatives 16. Diazotization of 16 gave the corresponding diazonium salts 17, which in the presence of CuCl as catalyst underwent an intramolecular Pschorr reaction to afford 4,5-didehydroguadiscines 18 (Scheme 4 and

Table 3. Synthesis and anti-melanogenic activity of 4,5-didehydroguadiscines 18 against B16 melanoma 4A5 cells through a CuCl-catalyzed Pschorr reaction.

Entry	Compound	R	R1	R2	Yield from 16 (%)	IC50 (µM) a
1	18a	OCH2O		MeO	--	4.9
2	18b	OCH2O		H	25	6.7
3	18c	MeO	H	H	30	5.0
4	18d	H	MeO	H	20	4.0
5	18e	H	H	H	29	3.1
6	18f	MeO	H	MeO	61	7.5
	Arbutin	--	--	--	--	174

^a The half-maximal inhibitory concentration (IC₅₀) of each compound was determined after 72 h of treatment with graded doses (1, 3, 10, and 30 μM). Untreated cells served as control, and cell viability was evaluated using the MTT assay.

).

Bioactivity Study

Compounds 18 were tested for melanogenesis-inhibitory effects against theophylline-stimulated B16 melanoma 4A5 cells in the concentration range of 1–30 μM, using the MTT assay. Results showed that 4,5-didehydroguadiscine derivatives 18b–f are highly potent, with IC₅₀ values ranging from 3.1 to 7.5 µM, with some of them showing similar or better activity compared to the naturally occurring 4,5-didehydroguadiscine 18a (IC₅₀ = 4.9 μM, Table 3). Interestingly, the unsubstituted derivative 18e (R = R¹ = R² = H) exhibited the highest potency, with IC₅₀ = 3.1 µM, around 56-fold enhancement in activity relative to arbutin (IC₅₀ = 174 μM) [25], indicating that the absence of the O-substituents in 18 did not significantly affect the melanogenesis-inhibitory activity (Table 3).

2.2.3. Synthesis of the Methyl 6H-Benzo[e]naphtho[2,3-c][1,2]thiazine-10-Carboxylate 5,5-Dioxide 26

Cyclin-dependent kinase 4 (Cdk4) inhibition is a promising therapeutic strategy for mitigating neurodegeneration in Alzheimer’s disease (AD) [26]. The ester moiety of compound 26 was employed as a pivotal building block for the synthesis of Cdk4 inhibitors with potential neuroprotective activity (Scheme 5). The synthetic route began with 6-aminonaphthalene-2-carboxylic acid 20, which underwent Fischer esterification with 10% aqueous H₂SO₄ in MeOH, affording methyl ester 21. Subsequently, compound 21 was sulfonylated with 2-nitrobenzenesulfonyl chloride 22 in the presence of TEA in THF, yielding the N-sulfonyl derivative 23. Reduction of the nitro group of 23 with SnCl₂ in refluxing EtOH furnished the aniline derivative 24. Diazotization of 24 with sodium nitrite in a AcOH:HCl (3:1, v/v) mixture generated the diazonium salt 25, which underwent a copper-catalyzed Pschorr cyclization to yield the target dioxide 26 [26].

2.3. Gold-Catalyzed Pschorr Reaction

The fluorenone framework is widely present in bioactive molecules [27] and also serves as a building block in materials applications [28]. The classical approaches to fluorenone synthesis typically rely on Friedel–Crafts acylation or oxidation of fluorene derivatives. These methods employ strong acids, oxidants, or elevated temperatures [29,30]. An alternative strategy for the synthesis of structurally valuable fluorenones 31 employed aryldiazonium salts as electrophilic partners in an Au(I)-catalyzed oxidation/C–H activation/cyclization cascade [31]. In this process, the key aniline precursors 29 were prepared through a two-step sequence involving an initial palladium-catalyzed oxidative C–H coupling between acetanilides 27 and aromatic aldehydes 28, followed by hydrolysis of the acetamide (COMe) protecting group [32]. Subsequent diazotization of anilines 29 in the presence of tBuONO/HPF₆ afforded the aryldiazonium salts 30, which were isolated and stored in the dark. After optimization of the reaction conditions, the Pschorr cyclization was accomplished by subjecting the diazonium salts 30 to the Me₂SAuCl/terpy/ascorbic acid catalytic system, to form the desired fluorenones 31 (

Table 4. Synthesis of fluorenone derivatives 31 via a gold-catalyzed Pschorr cyclization using diazonium salts 30.

Entry	Compound	R	R1	Yield from 30 (%)
1	31a	H	H	74
2	31b	7-Me	H	74
3	31c	7-OMe	H	68
4	31d	7-F	H	45
5	31e	7-Cl	H	33
6	31f	H	3-F	71
7	31g	H	3-Br	79
8	31h	H	3-I	51
9	31i	H	3-CF3	53
10	31j	H	3-Me	62
11	31k	H	3-tBu	57
12	31l	H	3-(4-MeOC6H4)	92
13	31m	H	3-Mesityl	52
14	31n	H	3-(4-tBuC6H4)	60
15	31o	H	3-(1-Naphthyl)	54
16	31p	H	3-(4-CF3C6H4)	59
17	31q	H	3-(4-NO2C6H4)	49
18	31r	6-Me	3-Cl	66
19	31s	6-Me	3-Br	54
20	31t	6-Me	3-NO2	55
21	31u	7-Me	3-Cl	58
22	31v	7-OMe	3-Cl	53
23	31w	7-Cl	1-F	29
24	31x	7-Cl	3-Cl	20
25	31y	6-Me	3-OMe	85
26	31z			61
	31z′			12

(i) Pd(TFA)₂ (5 mol%), TBHP, PhMe, 90 °C, 24 h; (ii) MeOH, HCl, reflux, 4 h.

).

Substituent effect study showed that electron-donating groups on either one of the aryl rings of the aryldiazonium 30 significantly enhanced the efficiency of the reaction, whereas electron-withdrawing substituents markedly suppressed their reactivity (Table 4). The observed trend is consistent with an electrophilic aromatic substitution (S_EAr) mechanistic sequence, involving a C–H auration/activation step preceded by an η²-coordination with terpy ligand, in which the key Au(III) arene π-complex A (Figure 1) should be formed after an oxidation process [33].

3. Metal-Free-Catalyzed Pschorr Reaction

3.1. Brønsted Acid-Catalyzed Pschorr Reaction

3.1.1. Synthesis of Multicaulin

Multicaulin is a naturally occurring diterpenoid characterized by a phenanthrene core bearing a methoxy substituent at C–6, methyl groups at C–1 and C–2, and an isopropyl group at C–7, exhibiting notable antitubercular activity [34]. Its successful total synthesis has enabled detailed structure–activity relationship studies and facilitated the preparation of structurally related analogs, including compounds 40a and 40b (Scheme 6) [34]. The synthetic sequence commenced with reduction of ester 32 using LiAlH₄ in THF to furnish alcohol 33 which was converted to benzyl bromide 34 by an Appel-type bromination with PBr₃ in DCM. Treatment of 34 with PPh₃ in refluxing ACN generated the phosphonium salt 35, which was employed directly in the next step without purification. A Wittig olefination between phosphonium salt 35 and 2-nitrobenzaldehyde 36 afforded an inseparable mixture of (E/Z)-nitrostilbene 37, which was subsequently hydrogenated over Pd/C in MeOH to deliver aniline derivative 38 in an overall 86% yield across three steps. Diazotization of aniline 38 using isopentyl nitrite in the presence of sulfuric acid generated the corresponding diazonium salt 39, which underwent a Pschorr reaction to afford an inseparable mixture of products 40a/40b in 3:1 regioisomeric ratio. This outcome reflects the operation of two competing intramolecular aryl–aryl bond-forming pathways occurring at positions “a” and “b” from the diazonium intermediate 39 (Scheme 6).

Bioactivity Study

The inseparable mixture of compounds 40a/40b was subsequently evaluated against Mycobacterium smegmatis, Mycobacterium bovis, Mycobacterium szulgai, Mycobacterium gastri, Mycobacterium simiae, and Mycobacterium tuberculosis H37Ra, using streptomycin as the reference control (

Table 5. Antimycobacterial activity of the mixture of phenanthrene compounds 40a/40b.

Entry	Strain	40a/40b (MIC µM)	Streptomycin (MIC µM)
1	M. smegmatis	>991.50	2.68
2	M. bovis	991.50	0.67
3	M. szulgai	>991.50	1.30
4	M. gastri	>991.50	0.17
5	M. simiae	>991.50	2.68
6	M. tuberculosis (H37Ra)	>991.50	0.84

) [34]. Although compounds 40 displayed no significant antimycobacterial activity, with MIC values ranging from 991.50 to >991.50 µM, markedly lower than those of streptomycin (MIC = 0.17–2.68 µM), their structures proved to be valuable synthetic intermediates used as key precursors for the preparation of multicaulin- and miltirone-like compounds, which exhibited remarkable antimycobacterial activity.

3.2. Ionic Liquid (IL)-Catalyzed Pschorr Reaction

The Pschorr reaction of arenediazonium salts 30 was investigated in [BMIM][TfO] and [BMIM][Tf₂N], with particular focus on substituent effects on product distribution (

Table 6. Product distribution resulting from both Pschorr and dediazoniation reactions of diazonium salts 30 in the presence of [BMIM][TfO].

Entry	R	T (°C)	Time (h)	Yield Ratio a	Total Yield of 31 and 41 (%) a
1	H	50	6	31a:41a (66:34)	79
2	Me	80	1.5	31b:41b (58:42)	84
3	MeO	80	2	31c:41c (53:47)	78
4	Cl	80	1	31d:41d (42:58)	74

^a The yield ratio was determined by ¹H NMR analysis.

and

Table 7. Product distribution from dediazoniation of salts 30 in [BMIM][Tf₂N].

Entry	R	Temp (°C)	Time (h)	Yield Ratio a	Total Yield of 31, 42, and 43 (%) a
1	H	50	6	31a:42a:43a (85:15:<1)	91
2	Me	80	1.5	31b:42b:43b (75:24:1)	94
3	MeO	80	2	31c:42c:43c (72:27:1)	84
4	Cl	80	1	31d:42d:43d (78:22:<1)	72

^a The yield ratio was determined by ¹H NMR analysis.

) [35]. Salts 30 were obtained by reacting their corresponding keto-anilines 29 with sodium nitrite in aq HBF₄. The ILs were prepared starting from [BMIM][Cl] by metathesis with LiOTf and LiNTf₂ [36,37,38]. Heating solutions of 30 in [BMIM][TfO] yielded mixtures of 9-fluorenone products 31 and substitution products 41 as determined by ¹H NMR (Table 6).

Analogously, mixtures of products 31 and substitution products 42 and 43 were obtained when diazonium salts 30 were heated in [BMIM][Tf₂N] (Table 7). In this case, the Pschorr products 31 were formed more selectively than in [BMIM][TfO], indicating a more facile electron transfer with [Tf₂N]. Preferential formation of 42 over 43 reflects the dominance of O-attack over N-attack. Additionally, the nature of the substituents (R = H, Me, MeO, Cl) had no significant influence on product distribution.

The observed product distributions reflect competing homolytic and heterolytic dediazoniations. Aryl radicals Ar• are typically involved in intramolecular cyclizations (Scheme 7, Equation (1)), affording fused systems like 31 via Pschorr reaction, while aryl cations Ar⁺ typically undergo substitution by counterion attack (Scheme 7, Equation (2)), affording substituted products like 41–43. As mentioned earlier, formation of products 41–43 reflects the ambident nucleophilic character of [OTf] and [NTf₂] counterions [16].

DFT computations were performed to estimate the influence of the IL on homolytic versus heterolytic processes with aryldiazonium salts 30 (Scheme 7) and the results suggested that the homolytic process is induced more readily in [BMIM][Tf₂N] than in [BMIM][TfO].

3.3. TEMPO-Catalyzed Pschorr Reaction

The 2-fluoro-5-nitrophenyldiazonium tetrafluoroborate 45 has emerged as an efficient Sanger-type reagent for the direct functionalization of aliphatic alcohols like 46 (Scheme 8) [39]. The diazonium salt 45 was synthesized from aniline 44 by diazotization with tBuONO in BF₃•OEt₂ and MTBE as solvent [40]. Owing to its strong electron-withdrawing character, diazonium salt 45 efficiently promoted reactions with weakly nucleophilic alcohols 46 in a mixture of CD₃CN:(CD₃)₂SO, to yield aryl–alkyl diazonium ethers 47 (Scheme 8). A subsequent TEMPO-promoted Pschorr cyclization of 47 furnished the tricyclic dibenzoxepanes 48 (Scheme 8), demonstrating, the utility of diazonium-mediated strategies for constructing oxygenated polycyclic frameworks.

3.4. Thermally Activated Pschorr Reaction

The benzoxanthene imide (BTI) framework is a key component in materials science and synthesis due to its use in textile dyes and applications such as organic photovoltaics, OLED/LEC and photodynamic therapy (PDT) [41,42].

Synthesis of a series of BTI-based potential luminescence and liquid crystal materials 55 was undertaken, focusing on synthesis of the regioisomeric brominated benzothioxanthene anhydrides 54a (p-BTA-Br) and 54b (m-BTA-Br), as key intermediates for those materials [43]. A one-pot, microwave-assisted, thermal Pschorr cyclization was employed as the key step of the synthetic process (Scheme 9). Thus, brominated naphthalene anhydride 49 was coupled via a S_NAr with bromoaminobenzenethiols 50 to form the corresponding aniline–thioether intermediates 51, which were subsequently converted in situ into the aryl diazonium salts 53 by treatment with isoamyl nitrite 52. The diazonium salts 53 underwent a Pschorr radical ring closure, by thermal decomposition in the reaction medium, to furnish the polycyclic brominated benzothioxanthene anhydrides 54a,b. Further synthetic steps converted the polycycles 54a,b into the expected BTI-based liquid crystal composites 55a,b (Scheme 9).

Polarized light optical microscopy (POM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) techniques and photophysical studies were used to confirm the structure and properties of the target BTIs 55. In general, these compounds exhibited favorable emissive properties while maintaining the inherent advantages of LCs [43].

In a further study, the same researchers developed a Pschorr-mediated synthetic strategy to obtain additional examples of N-annulated BTI derivatives 61 and 62 in a four-step sequence [44], improving a previous seven-step procedure [45]. The imidation of the brominated naphthalene anhydride 49 by treatment with 3-aminopentane 56 afforded the corresponding brominated imide 57. Subsequently, nucleophilic coupling of 57 with the aminothiophenol 50c (R = H) under basic conditions provided the key aniline–imidothioether precursor 58. This precursor was then subjected to Pschorr cyclization mediated by tertbutyl nitrite (through thermal decomposition of the diazonium salt intermediate 59) affording the unexpected nitro-benzothioxanthene imide (NO₂-BTI) 60. Compound 60 was then treated with either triphenylphosphine [46] or elemental sulfur [47] to deliver the corresponding N-annulated structure 61 (TCI) and the S-annulated structure 62 (TSI) respectively (Scheme 10) [44].

Formation of the nitro-derivative 60 (NO₂-BTI) demonstrates that alkyl nitrite could act as nitrating agent under these conditions, which would offer advantages relative to conventional nitration, especially during scale-up processes [48]. A plausible mechanism for the formation of 60 (Scheme 11) starts with nitrosation of aniline–imidothioether 58 with tBuONO to give the N-nitroso intermediate A, which upon dehydration is converted into the aryl diazonium salt 59. Then the alkoxide (tBuO⁻) present in the reaction medium reacts with the diazonium group to afford the activated radical species B, promoting N₂ extrusion and generating the key aryl radical C. This radical is delocalized into the aryl ring and can be trapped by NO₂, formed in situ by oxidation of NO arising from the thermal decomposition of tBuONO. Finally, rearomatization of the nitro-intermediate G delivers the nitro-compound 60 (NO₂-BTI).

4. Photoredox-Catalyzed Pschorr Reaction

Synthesis of 6H-Benzo[c]chromenes

An organic photoredox Pschorr reaction for the synthesis of 6H-benzo[c]chromenes 8 was developed by using the organic dye eosin Y as catalyst under irradiation by green light-emitting diodes (LEDs) (

Table 8. Synthesis of 6H-benzo[c]chromenes 8 via an eosin Y-promoted photoredox Pschorr reaction from 2-(benzyloxy)benzenediazonium tetrafluoroborates 4.

Entry	Compound	R	R1	Yield from 63 (%)
1	8a	H	H	90
2	8b	H	5-Me	95
3	8c	H	3-Me	48
4	8d + 8′-d	H	4-Me + 6-Me	(49:51) 98
5	8e + 8′-e	H	4-MeO + 6-MeO	(22:78) 73
6	8f	H	5-Cl	30
7	8g	8-Me	5-Me	88
8	8h	8-Me	H	90
9	8i	8-Me	3-Me	64
10	8j + 8′-j	8-Me	4-Me + 6-Me	(50:50) 77
11	8k + 8′-k	8-Me	4-MeO + 6-MeO	(24:76) 73
12	8l	8-Cl	H	72
13	8m	8-Cl	5-Me	57
14	8n	9-F	H	80
15	8o	8-NO2	H	29

(i): 1 (1.0 equiv), 2 (1.0 equiv), K₂CO₃, ACN, then, the obtained nitrobenzyloxy derivative (1.0 equiv), SnCl₂•H₂O, AcOEt; (ii): 63 (1.0 equiv), aq tBuONO (1.5 equiv), HBF₄ (1.5 equiv), 5 °C.

) [49]. The amino-ethers 63 were synthesized by a nucleophilic aromatic substitution (S_NAr) reaction between nitrophenols 1 and bromo-derivatives 2 in the presence of K₂CO₃, and subsequent reduction of the nitro group with SnCl₂•H₂O. Then, in situ diazotization of amines 63 with aq tBuONO in HBF₄ afforded the 2-(benzyloxy)benzenediazonium tetrafluoroborates 4 [19]. To continue with the synthesis of the target benzo[c]chromenes 8 an intramolecular Pschorr cyclization was undertaken. Optimization of the reaction conditions in terms of solvent, catalyst, irradiation, and concentrations established that the irradiation of the diazonium salts 4 with 36 W green LEDs in the presence of eosin Y in ACN gave the best yields of the cyclized products 8, tolerating various functional groups (Table 8). Control experiments confirmed that both light potency and eosin Y play central roles in the efficacy of the intramolecular photoredox cyclization.

Following the same procedures, diazonium salts 7c,g were obtained as described previously in Scheme 1. Subsequently, these starting materials were subjected to the optimized reaction conditions affording the corresponding 4-chloro- and 2-fluoro-6H-benzo[c]chromenes 9c and 9g, respectively, along with the reduction products 64c,g (Scheme 12).

Additionally, the robustness of this photoredox protocol was assessed by a gram-scale synthesis, as well as a one-pot synthesis of the 6H-benzo[c]chromene (8a) (R = H). In this strategy, the diazonium salt 4a was generated in situ by addition of tBuONO to the aniline 3a and subsequent irradiation of the reaction mixture under the established photoredox conditions afforded the expected product 8a as shown in Scheme 13.

A plausible mechanism for the intramolecular photoredox Pschorr cyclization of the diazonium salts 4 is depicted in Scheme 14. It involves reduction of 4 to the aryl radical A by the excited photoredox catalyst eosin Y* via single-electron transfer, while eosin Y is oxidized to eosin Y⁺. Then, intramolecular cyclization of A generates the radical intermediate B, which after oxidation with eosin Y⁺ regenerates the original eosin Y, completing the catalytic cycle and providing the aryl cation C, which subsequently is deprotonated by the BF₄^– counterion to afford the expected product 8 [49].

5. Pschorr-Inspired Benzannulations and Extensions—Formation of Spirocyclic Systems

5.1. Intramolecular Benzannulations

5.1.1. Synthesis of Fused-Hydro-Aromatic Systems by Intramolecular Ring Closure

Pyrazole-based heterocycles are important in medicinal and synthetic chemistry due to their broad range of biological activities and versatility as key intermediates for assembly of complex molecular architectures [50,51]. A synthetic sequence aimed at the synthesis of tricyclic pyrazolo-derivative 73 via a Pschorr ring closure began with the acylation of 1,3-dimethyl-1H-pyrazol-5-amine 65 using acetic anhydride to afford the corresponding acetamide 66 (Scheme 15) [52]. Subsequent N-methylation under basic conditions with methyl iodide furnished the N-methyl-derivative 67, which upon hydrolysis provided the N-methylated 5-aminopyrazole 68, whose acylation with 2-nitrobenzoyl chloride 69 afforded the 2-nitrobenzamide 70. Catalytic hydrogenation of 70 afforded the corresponding 2-amino-N-methylbenzamide 71, and subsequent diazotization of 71 in the presence of sulfuric acid generated the diazonium hydrogen sulfate 72, which was then subjected to a Pschorr cyclization in the presence of copper sulfate, sodium chloride, and ascorbic acid. Surprisingly this transformation did not afford the expected tricyclic pyrazolo-derivative 73; instead, a mixture of the non-separable chlorinated spirocyclic epimers 74/75, along with separable hydroxyl spirocyclic epimers 76/77, and the benzamide 78 were obtained (Scheme 15).

To further explore the scope and synthetic potential of the transformation described in Scheme 15, a complementary route was developed starting from the 2-nitrobenzamide precursor 79 (Scheme 16) [52]. Thus, treatment of 79 with hydrochloric acid and a large excess of potassium nitrite in acetic acid directly afforded the nitro-diazonium salt 80 [53]. Subsequent in situ conversion of intermediate 80 into the corresponding 4-chloropyrazole derivative 81 was achieved using CuSO₄•5H₂O, NaCl, and ascorbic acid as catalytic system, thus blocking the 4-position of the pyrazole moiety in 81. Reduction of the nitro group in 81 with iron in an acetic acid–water mixture afforded the aniline derivative 82, which was further subjected to diazotization to furnish the intermediate diazonium salt 83. Under identical Cu(II)/ascorbate-mediated radical conditions to those applied for the diazonium salt 80, a Pschorr-type cyclization of 83 delivered the dichlorinated spirocycle 84 (Scheme 16).

A plausible mechanism for the Cu(II)-catalyzed formation of the spirocycle 84 from diazonium salt intermediate 83 (Scheme 17) involves generation of the radical species A and subsequent ring closure to form radical species B which reacts with cuprous chloride to yield the dichlorinated spirocycle 84. The key role of the ascorbic acid is to reduce Cu(II) to Cu(I) which, in turn, reduces the diazonium ion 83 to a diazenyl radical. The latter intermediate decomposes to dinitrogen (N₂) and the phenyl radical A species [52].

Further studies on spirocyclization via Pschorr-type reaction examined the influence of (hetero)aromatic substituents tethered through an amide linker on the cyclization outcome (Scheme 18 and Scheme 19) [52]. Accordingly, amines 85 and 89 were subjected to diazotization with sulfuric acid and sodium nitrite, and the resulting diazonium salts 86 and 90 were exposed to CuSO₄•5H₂O, NaCl, and ascorbic acid to promote aryl radical formation. Under these conditions, diazonium salt 86 underwent a highly selective 5-exo-trig cyclization to give the spiro-system 87 (34%) as a trans/cis mixture, accompanied by trace amounts of the expected tricyclic Pschorr product 88 arising from a competing 6-endo-trig process (Scheme 18).

With diazonium salt 90, the Pschorr reaction product 91 (the 6-endo-trig mode) was not observed; instead, a 5-exo-trig cyclization prevailed, yielding methylisoindoline-1,3-dione 93 and the bis-spiro compound 94 (Scheme 19) [52]. In parallel, a competing 1,5-hydrogen shift from the N-methyl group in 90 accounted for the formation of the secondary amide 92 [54].

The products obtained in these transformations (Scheme 18 and Scheme 19) signify the interplay of radical cyclization kinetics, the electronic nature of the (hetero)aromatic acceptor, and the competing 1,5-H shift processes [54]. While the 5-exo-trig closure is generally favored, the alternative 6-endo-trig or hydrogen-shift pathways also operate depending on the substitution pattern. In this synthetic design, the Pschorr-type cyclization proved to be a valuable method for the synthesis of spirocyclic architectures 87 and 94.

In another study, the same authors investigated substrates with an inverted amide bridge between the pyrazole and phenyl rings [55]. The key -CONCH₃-based diazonium salt intermediate 98 was synthesized from the acyl chloride 95 and the o-nitroaniline 96 followed by the catalytic reduction of the nitro group to give 97, which after diazotization yielded the diazonium hydrogen sulfate 98 (Scheme 20). Intermediate 98 was then subjected to the Pschorr reaction, employing the redox system comprising CuSO₄, NaCl, and ascorbic acid. This resulted in three products 100–102 instead of the expected tricyclic product 99 (Scheme 20).

Formation of tricyclic dihydro-4H-pyrazolo[4,3-c]quinolin-4-one 102, a compound exhibiting affinity for the benzodiazepine receptor, via the Pschorr-type reaction is noteworthy. The suggested mechanism for its formation as a major component is depicted in Scheme 21, and involves intramolecular rearrangements involving a 1,4-transfer of the pyrazolyl group (pathway from A to C), followed by a Pschorr-type ring closure of the carbamoyl radical C.

Biological Studies

Compound 102 displaced [³H]flunitrazepam from its benzodiazepine receptor site in bovine brain membranes (IC₅₀ = 3.4 ± 0.2 μM), as well as exhibited antileukemic activity against HL-60 cell line inhibiting about 40% cell growth at 10 μM. These findings point to it being a potential antiproliferative agent, as well as a relevant pharmaceutical for CNS-related therapeutic research [55].

5.2. Aza-Pschorr-Type Reactions

The N-centered Blatter radical 104 is notable for its exceptional thermodynamic and kinetic stability, mainly due to extensive π-delocalization [56,57]. This radical and its derivatives have gained attention for their electrochemical properties and potential applications in the design of functional materials for molecular electronics, spintronics and photoconductive liquid crystals, among others [58,59,60]. The large torsion angle between the two π planes caused by rotation of the N-1-aryl group in radical 104 affects its molecular packing which is unfavorable for induction of liquid crystalline and semiconductive properties (Figure 2) [61]. This then calls for methods to convert the non-planar radical 104 to a planar radical analog 105a. Since previous anionic methods for the construction of the triazinephenoxazine core of the planar radical 105a were limiting, a radical-mediated aza-Pschorr-type cyclization approach was developed to synthesize 105a and its C(10)-functionalized derivatives [62].

The key amino-ether derivatives 108 were synthesized from 8-fluoro-3-phenyl-benzo[e][1,2,4]triazine (106) through an S_NAr with o-amino/-nitrophenolic compounds 107 in the presence of NaH/DMSO to afford the corresponding amino-ethers 108. After optimization of the reaction conditions, treatment of the amino-ethers 108 with tBuONO in chlorobenzene as solvent generated the corresponding diazonium salts 109, which under thermal dediazoniation furnished the planar Blatter radicals 105/110 (

Table 9. Synthesis of planar Blatter radicals 105/110 via a thermal aza-Pschorr-type cyclization from diazonium salts 109.

Entry	Compound	X	Yield from 108 (%)
1	105a	H	57–64
2	105b	CO2Me	57–64
3	105c	CN	68
4	105d	NO2	40–55
5	110	H	50–60

(i) 60% NaH, DMSO, 100 °C, 1 h. (ii) 60% NaH, DMSO, 100 °C, 1 day; then H₂ (2 bar), 10% Pd/C THF/EtOH, rt, overnight. (iii) amine 108 (0.25 mmol), PhCl (2 mL), tBuONO, rt to 70 °C, 15 to 45 min.

).

To shed light on the role of substituents on the electronic properties, namely stability, redox behavior, absorption spectra and spin distribution, synthesis of a larger series of C(10)-substituted derivatives of 105 was undertaken, starting with diversely substituted triazine-precursors 108 (synthesized according to Table 9). Cyclization via aza-Pschorr type (methods A/B via diazonium salts) was compared with photochemical (method C) and Bu₃SnH-assisted radical cyclization (method D,

Table 10. Synthesis of diversely C(10)-substituted planar Blatter radicals 105 via aza-Pschorr-type cyclizations and comparison with other cyclization methods starting from radical precursors 108.

Entry	Compound	X	Method	Yield (%)
1	105a	H	A (B)	57–64 (64–80)
2	105b	CO2Me	A (B)	48–55 (64−80)
3	105c	CN	A (B)	68 (60)
4	105d	NO2	A	40–55
5	105e	CF3	A	62
6	105f	OMe	A	52
7	105g	F	A	45
8	105h	Cl	A	55
9	105i	Br	A	18
10	105j	COMe	D	47–52
11	105k	CO2H	From 105b	90–95
12	105l	NH2	From 105d	82
13	105m	NHAc	From 105l	85
14	105n	I	A	42–47
15	105o	OBn	A (C)	29 (35–49)
16	105p	Ph	From 105n	61
17	105q	2-thienyl	From 105n	53
18	105r	C≡CPh	From 105n	50
19	105s	OAc	From 105j	15
20	105t	NHCOCF3	From 1051	73
21	105u	NHCO2Me	From 105l	68

(i) Method A: (a) tBuONO, rt to 70 °C, 15 min, then 45 min at 60–70 °C. (ii) Method B: PhCl, Zn powder, 1 h at 60 °C. (iii) Method C: 300 W halogen lamp, DCM. (iv) Method D: Bu₃SnH or TMS₃SiH, cat. AIBN, toluene, 4 h at 80 °C.

) [62,63,64,65,66]. Additionally, functional group transformations of the C(10)-amino/-nitro/-iodo derivatives were performed in some cases, starting from previously obtained planar radicals 105.

Further experiments and analytical techniques such as cyclic voltammetry, electron paramagnetic resonance spectroscopy, and correlation analysis were employed to characterize the planar Blatter radicals 105. The results indicated that electron-donating substituents C(10)–X lower the excitation energies and redox potential, and increase radical stability by increasing electron spin delocalization (Figure 3) and decreasing the N–H bond dissociation energy [66].

Further studies were aimed at the synthesis of π-extended liquid crystalline radicals 115. For this purpose, the intramolecular aza-Pschorr-type cyclization was employed as a key step to obtain the target radicals 115 [63]. The synthetic sequence started with the nitro-hydrazide 111, which upon reduction, cyclization, and oxidation afforded the 8-fluorobenzo[e][1,2,4]triazine 102 which was reacted with the sodium salt 107 in an S_NAr fashion to afford the triazolo-aniline 112.

Subjecting the triazolo-aniline 112 to diazotization with tBuONO followed by a homolytic dediazoniation furnished the planar Blatter radical intermediate 114, which was transformed into the target bent-core and π-extended liquid crystalline radicals 115 (Scheme 22).

The aza-Pschorr-type cyclization method was further utilized as a practical synthetic strategy for the construction of N-centered O- and S-peri-annulated planar Blatter radicals 105a and 116 [67]. Further studies aimed at developing a synthetic route to their N-centered N-peri-annulated radical analogs 117 (Figure 4) [68]. While the chalcogen atoms in O-peri- 105a and S-peri-annulated 116 radicals are divalent, the N(7) nitrogen atom in the N-peri-annulated radical analogs 117 is trivalent, for which the R-substituent connected to this atom could be used to tune the electronic system in 117.

Two complementary synthetic approaches, namely the aza-Pschorr-type cyclization and photocyclization, were considered for the synthesis of the N-peri-annulated radicals 117 [68]. Since several attempts to obtain the N-R nitro-precursor 119a (R = H) by aza-Pschorr-type cyclization failed, a Pd-catalyzed C−N cross-coupling reaction of 8-bromo-[1,2,4]triazine 118 with o-nitroaniline 96 in the presence of Pd₂(dba)₃/Cs₂CO₃ was used instead, to produce the desired intermediate product 119a as red crystals (Scheme 23). N-methylation using MeI/NaH afforded the N-methyl nitro-derivative 120b and catalytic reduction of this compound with H₂/Pd/C afforded the corresponding the N-methylamino-derivative 121b, while acetylation of nitroaniline 119a with Ac₂O/ZnCl₂ generated the N-acetyl derivative 120c.

Attempts to reduce the nitro group, in absence of HCl, afforded an inseparable mixture of the N-acetyl-aniline 121c and the imidazole side-product 122 (Scheme 23). When the reduction of 120c was carried out in the presence of catalytic HCl, the side-product 122 was isolated in near-quantitative yield.

Using 121b as precursor, the synthesis of the target N-peri-annulated planar radical 117b was attempted by employing an aza-Pschorr-type cyclization, via treatment of the N-methylamino precursor 121b with tBuONO, followed by thermal decomposition of the diazonium salt intermediate 123b. However, 121b did not lead to the N-peri-annulated radical 117b (R = Me); instead, two products, namely the zwitterionic species 124 and the fused carbazole 125, were isolated (Scheme 24).

Although the expected N-peri-annulated radical 117b was not isolated from the thermal aza-Pschorr-type cyclization, the isolation of the zwitterionic species 124 indicated that 117b must have been formed as a short-lived intermediate, suffering a demethylation under the thermal conditions. Similar results were obtained from the photochemical reaction, which also converted the nitro-compound 120b into the zwitterionic species 124 [68].

Formation of the zwitterionic species 124 and the fused carbazole derivative 125 could proceed through two competing processes involving the initial formation of the N-methylamino-radical species 117b, which could either cyclize at the N(1) position, leading to the expected N-peri-annulated radical 117b—whose decomposition, accompanied by demethylation, leads to 124—or alternatively cyclize at the C(7), generating the tetracyclic radical 127, which is transformed into 125 after homolytic dehydrogenation and re-aromatization (Scheme 25).

DFT calculations were in concert, showing that the activation energy required for N(1) attack to form species 117b is lower (by 1.35 kcal mol⁻¹) than that for the C(7) attack to form species 127. The difference in the activation energies correlates with the observed relative yields of the zwitterionic product 124 and the fused carbazole derivative 125 [68].

5.3. Organoboronic Acids as Novel Precursors for Pschorr-Type Cyclization

Synthesis of Fluorenones and Dibenzofuranes

Whereas the iron- or copper-catalyzed Pschorr cyclization of arenediazonium salts constitutes a classical method to access hetero-PAHs, including fluorenones and dibenzofurans, development of newer methods that avoid the use of diazonium salts has received recent attention. In this connection organoboronic acids were introduced as novel precursors for borono-Pschorr-type cyclization [69].

The synthetic sequence for the substituted fluorenones 31 started with preparation of the brominated diarylketones 129 from a three-step procedure (i–iii) starting with the aryl halides 128 (

Table 11. Synthesis of substituted fluorenones 31 from trifluoroborates 130 via an AgNO₃/K₂S₂O₈-catalyzed borono-Pschorr-type cyclization.

Entry	Compound	R	X	Y	Yield from 130 (%)
1	31a	H	CH	CH	41
2	31b	3-CN	CH	CH	55
3	31c	3-F	CH	CH	50
4	31d	3-OMe	CH	CH	43
5	31e	3-CO2Me	CH	CH	67
6	31f	1,3-diCF3	CH	CH	61
7	31g	2,3,4-tri-F	CH	CH	71
8	31h	H	N	CH	64 (1.4:1; 31h:31i)
9	31i	H	CH	N

(i): iPrMgCl or nBuLi (1.0–1.05 mmol), THF (1–10 mL), −78 °C to 0 °C, 30 min to 3 h; (ii): o-bromobenzaldehyde/bromoformylpyridines (0.9–1.05 mmol), −78 °C to rt, 30 min to 3 h; (iii): MnO₂ (10.0 mmol), DCM; (iv): pinacol borane (1.5 mmol), MeOH (2 mL), PdCl₂(ACN)₂ (0.02 mmol), SPhos (0.08 mmol), TEA (1.5 mmol), p-dioxane (0.6 mL), MWI (110 °C), (1–2 h); (v): KHF₂ (3 equiv), rt, 30 min.

). Subsequent treatment of bromo-ketones 129 with pinacol borane catalyzed by PdCl₂ and reaction with KHF₂ gave the corresponding potassium trifluoroborate salts 130, as key intermediates for the borono-Pschorr-type cyclization. Reaction of trifluoroborates 130 with catalytic silver nitrate and stoichiometric potassium persulfate in aqueous medium [70] afforded the target fluorenones 31 as described in Table 11.

Alternatively, fluorenones 31 were synthesized by reaction of aryl Grignard reagents 131 with o-formyl pinacol boronate ester 132 followed by aq KHF₂, generating the alcohol intermediates 133. The hydroxy-trifluoroborate salts 133, upon treatment with AgNO₃/K₂S₂O₈, afforded fluorenones 31 (Scheme 26) [69].

This protocol was then extended to the synthesis of dibenzofurans 136, directly from the key organoboronic acids 135. This procedure involved the previous preparation of 135 from a three-step procedure (i–iii) starting with the o-iodo- or o-bromo-diarylethers 134, and subsequently subjecting organoboronic acids 135 to the established AgNO₃/K₂S₂O₈-catalyzed reaction conditions, to yield the benzofurans 136 (

Table 12. Synthesis of substituted dibenzofurans 136 from organoboronic acids 135 via AgNO₃/K₂S₂O₈-catalyzed Pschorr-type cyclization.

Entry	Compound	R	Yield (%)
1	136a	2-CF3	73
2	136b	2-F	69
3	136c	2-CO2Me	57
4	136d	H	65
5	136e	1-OMe	41 (1:5; 136e:136f)
6	136f	3-OMe

(i): for 134a,b, X = I: 134a,b (1.0 equiv) in PhH (10 mL), (iPrO)₃B (1.2 equiv) in THF-toluene (3.4 mL) at −78 °C, nBuLi (1.2 equiv in hexanes), −78 °C to −20 °C, 60 min, then 2N HCl (3 mL); (ii): for 134c, X = I: 134c (1.0 equiv), (iPrO)₃B (1.9 equiv) in THF (1.4 mL) at 0 °C, iPrMgCl•LiCl (1.1 equiv in THF), 0 °C, 30 min, then 0.5 M HCl; (iii): for 134d, X = Br: 134d (1.0 equiv), nBuLi (1.05 equiv in THF), anh THF (9.5 mL) at −78 °C, 45 min; (iPrO)₃B (2.5 equiv), −78 °C to rt, 2h, then Et₂O (9 mL) and 1N HCl (9 mL) at 0 °C.

) [69].

6. Summary and Future Outlook

The present review highlights and underscores the recent developments in the Pschorr reaction and its offshoots, and their application in the synthesis of PAHs and hetero-PAHs. Following the synthesis of the key diazonium salts, dediazoniation is achieved by a variety of methods, namely by metal catalysis, metal-free, thermally, or by photoredox chemistry, to form the aryl radical intermediates. These approaches are utilized to develop more efficient synthetic routes to important small-molecule bioactive compounds. The Pschorr-inspired benzannulation methods and their off-shoots, namely the aza-Pschorr and the borono-Pschorr cyclizations, are noteworthy areas deserving further expansion. Looking globally, it is highly notable how this classical method for aryl radical generation and annulation, starting from the diazonium salts, has inspired the development of numerous more modern methods and off-shoots that provide shorter, more efficient synthetic routes to sought-after bioactive compounds.