Synthesis of 2H-Indazoles by the [3 + 2] Dipolar Cycloaddition of Sydnones with Arynes

Abstract

A rapid and efficient synthesis of 2H-indazoles has been developed using a [3 + 2] dipolar cycloaddition of sydnones and arynes. A series of 2H-indazoles have been prepared in good to excellent yields using this protocol, and subsequent Pd-catalyzed coupling reactions can be applied to the halogenated products to generate a structurally diverse library of indazoles.

Introduction

The synthesis of heterocyclic compounds has attracted significant attention for decades. Among the various heterocycles, the indazole system has received significant attention due to its diverse bioactivity.¹ Although a number of methods for the preparation of indazoles are known, most methods target 1H-indazoles. Those focused on the selective and efficient preparation of 2H-indazoles, which also appear to have pharmaceutical promise,² remain limited. Recently, significant efforts have been devoted to the development of synthetic routes towards 2H-indazoles,³ as highlighted by the elegant chemistry developed by Halland (eq 1)^3a and Song (eq 2).^3b However, it should be noted that most of these methods still have significant limitations. Thus, new routes are still desirable.

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Our two groups have extensive ongoing research programs in aryne chemistry directed toward biologically important heterocycles, including approaches involving Pd-catalyzed annulation reactions,⁴ electrophilic and nucleophilic reactions,⁵ inter- or intramolecular annulation reactions,⁶ and insertion reactions.⁷ Aryne dipolar cycloadditions have provided synthetically useful methods for the synthesis of benzotriazoles,⁸ indazoles,⁹ and benzisoxazoles¹⁰ by reactions with azides, diazo compounds, and nitrile oxides, respectively.

For the synthesis of 2H-indazoles, we have previously communicated a [3 + 2] cycloaddition approach involving arynes and readily accessible sydnones (eq 3).¹¹ This chemistry, which offers very mild reaction conditions, high yields, and no contamination by 1H-indazoles, presumably involves an initial [3 + 2] cycloaddition to afford a bicyclic adduct, followed by spontaneous extrusion of a molecule of CO₂ in a retro-[4 + 2] fashion. Herein, we wish to report the full details on this project, and demonstrate its potential application to the construction of a small library utilizing palladium-catalyzed cross-couplings of halogenated 2H-indazoles prepared by our methodology.

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Results and Discussion

Preparation of the sydnones

Sydnones are readily prepared from the corresponding amino acids¹² by a sequence which involves N-nitrosation/cyclodehydration. Three different protocols, namely Protocol 1A [1.5 equiv of NaNO₂, 0 °C, 1 h, then acidify], Protocol 1B [2.0 equiv of NaNO₂, HCl, then 0 °C, 1 h], and Protocol 1C [1.5 equiv of i-amyl nitrite, DME, rt, 2 d] have been used in the nitrosation step, and two other protocols, namely 2A [Ac₂O as solvent, 110 °C, 2 h] and 2B [2 equiv of TFAA, Et₂O, rt, 2 h] have been used for the cyclodehydration step. A variety of sydnones have been synthesized starting from readily available amino acids (Scheme 1, see the Experimental Section for details). However, preparation of some sydnones, especially those with an alkyl group at the C-4 position have not been successful.

Scheme 1.

Synthesis of Sydnones.

Sydnones not readily derived from amino acids can be accessed by further functionalization of preformed monosubstituted sydnones. Thus, arylation and vinylation at the C-4 position of sydnones can be achieved from monosubstituted sydnones by Pd-catalyzed cross-coupling with aryl or vinylic halides using literature procedures (eq 4).¹³ Alkynylation at the C-4 position can be performed using the same protocol or by oxidative coupling with terminal alkynes (eq 5).¹⁴ Monosubstituted sydnones can also be iodinated¹⁵ or acylated¹⁶ at the C-4 position by reacting sydnones with ICl buffered with NaOAc/AcOH (eq 6) or acetic anhydride combined with NBS (eq 7) respectively.

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Reaction optimization

The reaction of o-(trimethylsilyl)phenyl triflate (1a) and N-phenylsydnone (2a) was investigated as the model reaction for optimization (Table 1). In the beginning, we found that using CsF in acetonitrile only afforded a 69% yield of 3aa with incomplete conversion of 2a, even upon a prolonged reaction time (entry 1). Running the reaction in THF led to complete conversion with a much improved 90% yield (entry 2). We quickly found that better results and shorter reaction times could be realized by changing the fluoride source from CsF to TBAF (entries 3 and 4). With this change, THF and acetonitrile exhibited no apparent difference in yields. However, THF is slightly preferred, because it appeared to afford a pure product (white vs. yellow in acetonitrile). In addition, when using THF as the solvent, the loadings of both 1a and fluoride could be reduced while maintaining a near quantitative yield (entries 5 and 6). The reaction provides a clean, spot-to-spot transformation with perhaps only a trace of the starting material; no other spots were observed on TLC analysis. This sydnone-aryne cycloaddition appears to represent one of the best approaches to 2H-indazoles in terms of efficiency and yield. The reaction conditions reported in Table 1, entries 5 and 6, which employ the same stoichiometry and concentration, but use of either solid TBAF or a THF solution of TBAF afford similar results. Thus, the procedures reported in entries 5 and 6 have been chosen as our standard reaction conditions for our study of additional substrates.

Table 1. Reaction Optimization^a.

entry	1a (equiv)	fluoride source (equiv)	solvent	T (°C) /time (h)	yieldb (%)
1	1.5	CsF (2.5)	MeCN	rt, 36	69c
2	1.5	CsF (2.5)	THF	70, 24	90
3d	1.5	TBAF (2.5)	MeCN	rt, 12	95e
4d	1.5	TBAF (2.5)	THF	rt, 12	94
5d	1.2	TBAF (1.5)	THF	rt, 12	98
6f	1.2	TBAF (1.5)	THF	rt, 12	97

^aAll reactions were carried out on a 0.4 mmol scale at 0.1 M concentration.

^bIsolated yield.

^cIncomplete conversion of 2a even after 2 days.

^dSolid anhydrous TBAF was used.

^eThe product is significantly yellow, although no apparent impurity was detected by ¹H NMR spectroscopy.

^fA THF solution of TBAF (1 M) was used.

Scope and limitations

The scope and limitations of our approach to 2H-indazoles have been tested, first using a range of structurally diverse sydnones (Table 2). For monosubstituted sydnones with an aryl group, the reaction smoothly afforded excellent yields of the corresponding 2H-indazoles (entries 1-6), with a variety of functional groups tolerated, including halogens (entries 2 and 3), and alkyl (entry 4), ether (entry 5), and acetal (entry 6) groups. However, the electron deficient N-(4-nitrophenyl)sydnone 2g (entry 7) was found to be unreactive. Even with the addition of a second batch of 1.2 equiv of 1a after the first 1.2 equiv of 1a was consumed, 2g remained unreacted. N-Alkylsydnones (entries 8 and 9) also worked well under our reaction conditions, but in somewhat lower yields.

Table 2. Synthesis of 2H-Indazoles from Benzyne and Sydnones^a.

entry	sydnone	product	yieldb (%)	entry	sydnone	product	yieldb (%)
1			98	12			79
2			95	13			71
3			93	14			90
4			94	15			93
5			92	16			91
6			91	17			∼79e
7			tracec	18			72f
8			77	19			70g
9			70	20			88
10			70	21			90
11			63d	22			n.r.h

^aAll reactions were carried out on approximately 0.4 mmol of sydnone at a concentration of 0.1 M.

^bIsolated yield.

^cA trace amount of product was detected by GC-MS. Substrate 2g was still unreactive upon heating.

^dThis reaction was performed with 1.6 equiv of 1a and 2.4 equiv of TBAF.

^eThe reaction afforded a 52% yield of pure 3aq, together with another fraction of impure 3aq (32% by weight, approximately 80-85% purity) that was very hard to purify.

^fWith 15% recovery of 2r.

^gWith 19% recovery of 2s.

^hWith total recovery of 2v, 1a was consumed. Substrate 2v was still unreactive upon heating.

With substitution in the C-4 position of the sydnone, we have observed limited success with alkyl groups. Except for the proline-derived sydnone 2j (entry 10), which has the 3- and 4-substitution tethered into a ring, other sydnones were found unstable under our reaction conditions and afforded a fairly complex reaction mixture in the end. For example, sydnone 2k derived from leucine (entry 11) afforded only a 23% yield with ∼10% recovery of the sydnone under our standard conditions, and 1.6 equiv of 1a and 2.4 equiv of TBAF had to be employed for the full conversion of 2k. On the other hand, sydnones with sp²- or sp- carbon units in the C-4 position, including a vinyl group (entry 12), different aryl groups varying in their electronics (entries 13-16), different heterocyclic groups (entries 17 and 18), and an alkynyl group (entry 19), were all tolerated and the desired products were obtained in good to excellent yields, although in some cases (entries 18 and 19), incomplete conversion was observed. Successful substitution at the C-4 position of the sydnone has been extended to halogens, as illustrated in sydnones 2t and 2u (entries 20 and 21), where 88% and 90% yields have been obtained. However, substitution of other electron-withdrawing groups at the C-4 position has not been tolerated. For example, 4-acetylsydnone 2v was found to be unreactive with benzyne under our standard conditions (entry 22), leading to complete recovery of the starting sydnone. The adverse effect of electron-withdrawing groups has also been observed in entry 13, where a lower yield was obtained.

Next, a variety of different aryne precursors have been tested under our optimized reaction conditions (Table 3). As can be seen, excellent yields can be achieved regardless of the aryne structure. Symmetrical aryne precursors 1b and 1c have been converted to the corresponding 2H-indazoles 3ba (entry 1) and 3ca (entry 2), respectively in almost quantitative yields. Unsymmetrical aryne precursor 1d, which is neither electronically nor sterically biased, afforded mixtures of two possible regioisomers in nearly equal amounts (entry 3). Unsymmetrical aryne precursor 1e, which is partially biased electronically, led to an inseparable mixture of two isomers in a 1 : 0.8 ratio (entry 4). Unsymmetrical aryne precursor 1f, which is slightly biased by sterics, led to an inseparable mixture of two isomers in a 1 : 0.7 ratio (entry 5). An unsymmetrical naphthalyne precursor 1g was also reactive and led to an inseparable mixture of two isomers in equal amounts (entry 6). However, 2,3-pyridyne precursor 1h¹⁷ proved unsuccessful using our standard reaction conditions. We observed that all sydnone starting material was recovered when compound 1h was consumed (entry 7).

Table 3. Reaction with Other Aryne Precursors^a.

entry	sydnone	aryne precursor	product	yieldb (%)
1	Ar=PH 2a			97
2				95
3				93c
4				99d
5				98e
6				91f
7				0g
8				33h
				40
9	Ar=PH 2d			44i
				42i

^aAll reactions were carried out on 0.4 mmol of sydnone at a concentration of 0.1 M.

^bIsolated yield.

^cA 1:1 mixture of the 5-Me isomer and the 6-Me isomer was obtained.

^dAn inseparable 0.8:1 mixture of two isomers (5-MeO and 6-MeO) was obtained. The major isomer was not identified.

^eA 0.7:1 mixture of two inseparable isomers (4-Me and 7-Me) was obtained. The major isomer was not identified.

^fA 1:1 mixture of 3ga and 3ga' was obtained.

^gAll sydnone starting material was recovered when precursor 1h was consumed.

^hSee the Supporting Information for the structure assignment.

ⁱThe structures were assigned based on the polarity and ¹H NMR coupling pattern of the two isomers obtained from entry 6.

An interesting observation was made when we carried out the reaction using the unsymmetrical aryne precursor 1i, which is both sterically and electronically biased. While we isolated two products, we were only able to assign one as the 4-MeO isomer (3ia) (33% yield) through extensive NMR spectroscopic analysis and comparison with literature values.^11,18 We were unable to identify the other product. While HRMS suggested the identity as the desired regioisomeric product, the presence of extra aromatic protons, as well as two aliphatic methyl groups in the ¹H NMR spectrum, clearly suggested otherwise. It was not until we reacted 1i with another sydnone 2d that we realized what had happened. In the latter reaction, we again obtained two products. One was the desired 4-MeO isomer (3id) in a 44% yield, and the other product was again unidentified. However, we were able to observe exactly the same extra aromatic protons and exactly the same extra methyl signals that were observed in the previously unidentified product, but here the integration no longer involved integers. That clearly suggested that these “unidentified” products were in fact mixtures of two compounds. The mixture obtained from 1i and 2a involved approximately a 1:1 ratio of two products. Therefore, the HRMS information was correct. The “unidentified” product from 1i and 2a actually contained the 7-MeO isomer 3ia'. The other component in the mixture was later attributed to m-anisidine based on ¹H NMR spectral analysis and comparison with literature values. The existence of m-anisidine was also confirmed by GC-MS. Thus, by stirring this “unidentified” product with an excess of acetic anhydride and pyridine, followed by a regular work-up and silica gel chromatography, the pure 7-MeO isomer (3ia') could be obtained in a 40% yield. The ¹H NMR spectral data now matched the literature values.¹⁸ Similarly, compound 3id', the 7-MeO isomer from the reaction of 1i and 2d, could be isolated pure in about a 42% yield.

The regioselectivity in this cycloaddition, especially with the aryne derived from 1i, can be explained as shown in Scheme 2. For a sydnone, there are three resonance structures (A, B, and C, Scheme 2), and cycloaddition with the aryne should arise from the latter two. Since the aryne derived from 1i is known to be attacked preferentially by nucleophiles at the meta position (with respect to the OMe group) for both electronic and steric reasons,¹⁹ resonance structure B should lead to formation of the 7-OMe regioisomer 3ia', while resonance structure C should lead to formation of the 4-OMe regioisomer 3ia. While we typically draw the structure of sydnones as either A or B, computational chemists long ago realized that despite the enolate nature and the observed nucleophilic reactivity of C-4, the N-2 position actually carries a significant negative charge²⁰ and may serve as the nucleophile in the aryne reaction. Although the charge distribution of sydnones has been controversial,²¹ experimental results involving the cycloaddition of sydnones with unsymmetrical alkynes have clearly suggested that both N-2 and C-4 can react as the nucleophilic site.²² Moreover, the molecular orbital analysis of sydnones indicates that the LUMO of sydnones has very similar coefficients for N-2 and C-4,²³ rendering the N-2 and C-4 positions of a sydnone similar in reactivity. All these literature results support the formation of both isomers 3ia and 3ia' through cycloaddition, and the side-product, m-anisidine, appears to arise from a separate path during the formation of isomer 3ia. Possibly, due to steric hindrance of the methoxy group, the [3 + 2] cycloaddition to form 3ia is partially disrupted and therefore occurs stepwise, which stops at betaine D.²⁴ The addition of water may lead to the formation of E, which is attacked by hydroxide to form a ring-opened intermediate F. Intermediate F can further decompose to nitroso compound G, which is then reduced to m-anisidine.

Scheme 2.

Regioselectivity in the Cycloaddition Reaction and Proposed Mechanism for the Formation of m-Anisidine.

Mechanistic investigation

To gain further insight into this reaction, we conducted a brief Density Functional Theory and ab initio calculation of the reaction path using Gaussian 09. Geometry optimizations were performed with hybrid B3LYP functions in conjunction with the 6-31G(d) basis set. Higher-level relative energies were computed at the MP2/6-311+G(d,p) level based on the B3LYP/6-31G(d) optimized geometries. The schematic potential energy surface of the reaction with zero-point energy corrections is plotted in Figure 1. As can be seen, the initial [3 + 2] cycloaddition is an exothermic step. A subsequent retro-[4 + 2] reaction is again exothermic. Since we were not able to find the transition states of these cycloaddition and cycloreversion processes, a relatively smooth potential energy surface may exist.

Figure 1.

Schematic potential energy surface with zero-point energy (ZPE) corrections at the MP2/6-311+G(d,p) level (units in kJ mol^-1). The values in parentheses are those obtained at the B3LYP/6-31G(d) level. The energy of the reactants is set to zero as a reference.

Elaboration of 2H-Indazoles

As our approach to 2H-indazoles tolerates halogen substituents, those halogen atoms offer an ideal site for further elaboration by subsequent Pd-catalyzed cross-couplings. Such a strategy can quickly afford a library of structurally diverse, highly functionalized 2H-indazoles. In this regard, we have demonstrated the feasibility of such elaborations by converting 3at to the corresponding 3-aryl- and 3-(1-alkynyl)-2H-indazoles using Suzuki-Miyaura²⁵ and Sonogashira²⁶ reactions, respectively (Scheme 3).²⁷ By modifying the structure of the sydnones and arynes,²⁸ this approach can be easily exploited to provide more derivatives for potential biological activity screening. It should be noted that our direct new synthesis of alkynylsydnones¹⁴ is unable to prepare indazoles like 5at, and, therefore, the route described in Scheme 3 provides an effective route towards such compounds.

Scheme 3.

Suzuki-Miyaura and Sonogashira Coupling of 2H-Indazoles

Conclusions

This work affords an efficient, new, synthetic route to 2H-indazoles by the [3 + 2] cycloaddition of arynes and sydnones. The reaction is applicable to a variety of sydnones and silylaryl triflates and affords the corresponding cycloadducts in moderate to excellent yields. Compared with literature protocols, our approach offers very mild reaction conditions, high yields, and no contamination by 1H-indazoles. The resulting halogen-substituted 2H-indazoles are readily elaborated to more complex products using known organopalladium chemistry. Thus, the versatility of the cycloaddition and the tolerance of halogen make this methodology ideal for pharmaceutical chemistry.

Experimental Section

General Information

All reagents purchased from commercial sources were used as received. The solvents THF and MeCN were distilled over Na/benzophenone and CaH₂, respectively. The aryne precursors were used as received; those not commercially available were prepared according to literature procedures.^29,17 The sydnones were prepared as outlined below. The silica gel for column chromatography was supplied as 300-400 mesh or 230-400 mesh.³⁰ Powdered CsF was used as received and stored in a desiccator. TBAF (either 1 M in THF solution or anhydrous solid) was used as received. The solid TBAF was stored in a desiccator as well.

All melting points were measured and are uncorrected. The ¹H and ¹³C NMR spectra were recorded and are referenced to the residual solvent signals (7.26 ppm for ¹H in CDCl₃ and 77.2 ppm for ¹³C in CDCl₃).

All aryne cycloaddition reactions were carried out in oven-dried glassware and were magnetically stirred. A nitrogen atmosphere was not used, except that a balloon of nitrogen was attached to the reaction flask for the ventilation of CO₂.

Computational methods

All electronic structure calculations involved in this work utilized the Gaussian 09 program package.³¹ The geometries and frequencies of all the stationary points (including reactants, intermediates, and products) were calculated by Becke's three-parameter nonlocal-exchange functional with the nonlocal correlation functional of Lee-Yang-Parr (B3LYP) using the 6-31G(d) basis set. To get more reliable reaction energies, single-point corrections were performed by restricted or unrestricted second-order Møller-Plesset perturbation theory (MP2) with the 6-311+G(d, p) basis set using the B3LYP optimized geometries.

Preparation of the sydnones

All the sydnones were prepared as follows. Due to long T1 relaxation times, the acquisition of ¹³C NMR spectra for many sydnones could not be achieved, even after an overnight acquisition of 8000 scans on a 400 MHz instrument.

3-Phenylsydnone (2a)

^12a To a suspension of 5.00 g of N-phenylglycine (33 mmol) in 60 mL of water at 0 °C was added dropwise a solution of 3.50 g of NaNO₂ (51 mmol, 1.5 equiv) in 20 mL of water. The mixture was stirred at 0 °C for an additional 20 min and the resultant clear red solution was filtered while cold. A scoop of activated charcoal (ca. 200-300 mg) was added and the mixture was stirred for a few minutes before being filtered again. The intermediate N-nitroso-N-phenylglycine was precipitated from the filtrate by the addition of 10 mL of concentrated HCl and was then collected by filtration. It was washed with cold water and dried overnight under a high vacuum. The resulting solid was then dissolved in 25 mL of acetic anhydride and the mixture was heated to 100 °C for 1.5 h. After being cooled to room temperature, the resulting mixture was poured into 300 mL of ice water. A yellow solid formed, which was triturated by stirring for a few minutes in this cold water. The solid was filtered, washed thoroughly with water until no smell of acetic acid remained, and dried under a high vacuum overnight to afford 3.37 g of product (63% yield) as off-white crystals. This representative procedure for preparing sydnones from the corresponding amino acid is identified as Protocol 1: ¹H NMR (400 MHz, CDCl₃) δ 7.77-7.58 (m, 5 H), 6.75 (s, 1 H).

3-(4-Chlorophenyl)sydnone (2b)

A mixture of 5.10 g of 4-chloroaniline (40 mmol), 5.14 mL of ethyl chloroacetate (48 mmol, 1.2 equiv), and 6.53 g of NaOAc•3H₂O (48 mmol, 1.2 equiv) in 10 mL of ethanol was refluxed in a 100 °C oil bath overnight. After being cooled to room temperature, the mixture was poured into ice water, and the precipitate was filtered and dried. The crude product, N-(4-chlorophenyl)glycine ethyl ester, after crystallization from ethanol (4.01 g, 47% yield), was an off-white solid. It is strongly suggested that this intermediate be purified, either through recrystallization or column chromatography. The resulting ester (3.00 g, 14 mmol) was stirred with 1.01 g of LiOH (3.0 equiv) in 30 mL of THF/water (1:1) at 0 °C. After 2 h at 0 °C, the reaction mixture was gradually warmed up to room temperature, where the pH was adjusted to 3-4 with concentrated HCl. The precipitate was filtered and dried to afford 2.53 g of N-(4-chlorophenyl)glycine (98% yield) as an off-white solid (62% overall yield). This representative procedure for preparing an amino acid is identified as Route 1.³² Sydnone 2b was then synthesized as an off-white solid (72% overall yield) from the resulting amino acid following Protocol 1: ¹H NMR (400 MHz, CDCl₃) δ 7.74-7.67 (m, 2H), 7.64-7.56 (m, 2H), 6.79 (s, 1H).

3-(4-Bromophenyl)sydnone (2c)

The corresponding amino acid was prepared from 4-bromoaniline following Route 1 in a 65% overall yield. Sydnone 2c was synthesized from this amino acid following Protocol 1 as an off-white solid (50% overall yield): ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 2 H), 6.73 (s, 1 H).

3-(4-Methylphenyl)sydnone (2d)

The corresponding amino acid was prepared from 4-methylaniline following Route 1 in a 53% overall yield. Sydnone 2d was synthesized from this amino acid following Protocol 1 as an off-white to cream solid (60% overall yield): ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.2 Hz, 2 H), 6.72 (s, 1 H), 2.49 (s, 3 H).

3-(4-Methoxyphenyl)sydnone (2e)

The corresponding amino acid was prepared from 4-methoxylaniline following Route 1 in a 50% overall yield. Sydnone 2e was synthesized from this amino acid following Protocol 1 as an off-white solid (78% overall yield): ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 9.2 Hz, 2 H), 7.08 (d, J = 8.8 Hz, 2 H), 6.64 (s, 1 H), 3.91 (s, 3 H).

3-(3,4-Methylenedioxyphenyl)sydnone (2f)

The corresponding amino acid was prepared from 3,4-methylenedioxyaniline following Route 1 in a 60% overall yield. Sydnone 2f was synthesized from this amino acid following Protocol 1 as a brown solid (27% overall yield): ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.15 (m, 2 H), 6.96 (d, J = 8.3 Hz, 1 H), 6.64 (s, 1 H), 6.14 (s, 2 H).

3-(4-Nitrophenyl)sydnone (2g)

To 0.75 g of glycine (10 mmol) was added 10 mL of tetrabutylammonium hydroxide in methanol (1 M, 10 mmol, 1.0 equiv.); the solvent was removed under vacuum, and the residue was dissolved in 20 mL of DMSO. p-Fluoronitrobenzene (1.55 g, 11 mmol, 1.1 equiv) and 1.51 g of K₂CO₃ (11 mmol, 1.1 equiv) were added and the mixture was allowed to react under gentle warming (45 °C) with stirring until completion (monitored by TLC). The mixture was then poured into cold water, acidified with HCl, and extracted with ethyl acetate. The combined organic layers were evaporated under vacuum and the residue was purified by column chromatography (5:1 petroleum ether/EtOAc) to afford 1.2 g (65% yield) of the desired amino acid as a yellow solid.³³ Sydnone 2g was then synthesized from this amino acid following Protocol 1 as an off-white solid (36% overall yield): ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J = 8.8 Hz, 2 H), 7,98 (d, J = 8.8 Hz, 2 H), 6.84 (s, 1 H).

3-Methylsydnone (2h)

To an ice-cold solution of 6.7 mL of conc. HCl and 3.56 g of sarcosine (40 mmol) in 10 mL of water, was added a saturated solution of 5.52 g of NaNO₂ (80 mmol) in water. The mixture was stirred at 0 °C for 1 h and then extracted with ethyl acetate three times. The combined organic layers were concentrated under a vacuum to obtain N-nitroso-N-methylglycine as a yellow oil. The resulting oil was dissolved in 4 mL of dry ether and charged dropwise with ∼500 μL of trifluoroacetic anhydride (3.6 mmol, 1.8 equiv) at 0 °C. The reaction was stirred at 0 °C for a few minutes and gradually warmed to room temperature and stirred for another 1 h. The solvents were evaporated and the residue was dissolved in EtOAc. Solid NaHCO₃ was added to neutralize the excess acid and was removed by filtration. The EtOAc was evaporated and the residue was purified by chromatography (2:1 petroleum ether/EtOAc) to yield 300 mg of the desired sydnone (8 % overall yield) as a yellow oil. This representative precedure for preparing sydnones from the corresponding amino acid is identified as Protocol 2: ¹H NMR (400 MHz, CDCl₃) δ 6.32 (s, 1 H), 4.07 (s, 3 H).

3-Benzylsydnone (2i)

This sydnone was synthesized from N-benzylglycine as a white solid (39% overall yield) following Protocol 2: ¹H NMR (400 MHz, CDCl₃) δ 7.45 (overlap, 3 H), 7.39 (overlap, 2 H), 6.21 (s, 1 H), 5.36 (s, 2 H).

3,4-Cyclopenta[c]sydnone (2j)

This sydnone was prepared according to a literature procedure³⁴ as a brown oil (∼11% overall yield).

3-(4-Chlorophenyl)-4-(isobutyl)-sydnone (2k)

To a round-bottom flask equipped with a stir bar, was added 1.32 g of L-leucine (10 mmol), followed by 190 mg of CuI (1 mmol, 10 mol %), 3.04 g of anhydrous K₂CO₃ (22 mmol, 2.2 equiv.), 2.87 g of 4-bromochlorobenzene (15 mmol, 1.5 equiv.), and 9 mL of undistilled DMSO. The reaction system was flushed with nitrogen. The flask was sealed with a Teflon stopper and placed in a 70 °C oil bath. The suspension was vigorously stirred. After 15 h, the stirring was found to be difficult, and another 4 mL of DMSO was added. The reaction was stopped at 40 h when the color changed from a purple-brown to blue. The reaction was poured into ice water and concentrated HCl was added until the pH reached 3-4. The precipitate was filtered, washed thoroughly with cold water (slightly acidified by HCl to pH ∼4) and dried under a high vacuum to yield 2.6 g of crude N-(4-chlorophenyl)leucine as a slightly green solid (yield >100%).^12f,g It should be noted that this method did not work for Met or Thr. This crude amino acid was used in the next step without further purification.

To a solution of 500 mg (∼2 mmol considering possible impurities) of crude N-(4-chlorophenyl)leucine in 3 mL of undistilled DME was added dropwise ∼400 μL of isoamyl nitrite (3 mmol, 1.5 equiv) at room temperature. The mixture was allowed to stir for 2 d before the solvent was removed under reduced pressure. The solid was triturated with petroleum ether and filtered. The cake was washed with petroleum ether and air dried. The solid was dissolved in 4 mL of dry ether and was charged dropwise with ∼500 μL of trifluoroacetic anhydride (3.6 mmol, 1.8 equiv) at 0 °C. The reaction was stirred at 0 °C for a few minutes and gradually warmed to room temperature and stirred for another 1 h. The solvents were evaporated and the residue was dissolved in EtOAc. The excess acid present was neutralized by the addition of solid NaHCO₃, which was then removed by filtration. The EtOAc was evaporated and the residue was purified by chromatography (3:1 petroleum ether/EtOAc) to yield 130 mg of the desired sydnone (26% overall yield) as a light brown oil: ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.7 Hz, 2 H), 2.37 (d, J = 7.4 Hz, 2 H), 1.88 (dt, J = 13.6, 6.8 Hz, 1 H), 0.80 (d, J = 6.6 Hz, 6 H).

3-(4-Chlorophenyl)-4-(4-methoxyphenyl)sydnone (2o)¹³

To a mixture of 197 mg of N-(4-chlorophenyl)sydnone (1.0 mmol), 351 mg of 4-iodoanisole (1.5 mmol, 1.5 equiv), 11 mg of Pd(OAc)₂ (0.05 mmol, 5 mol %), 26 mg of PPh₃ (0.1 mmol, 10 mol %), and 276 mg of anhydrous K₂CO₃ in a 10 mL round-bottom flask was added 2 mL of undistilled DMF. The flask was fitted with an air condenser and placed in a 120 °C oil bath overnight, during which time the reaction mixture was stirred open to the air. The mixture was cooled to room temperature, poured into 30 mL of water, and extracted three times with EtOAc. The combined extracts were washed once with brine, dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography (petroleum ether/EtOAc) to afford 145 mg of 2o as a yellow solid (48% yield). This representative procedure for preparing functionalized sydnones is identified as Protocol 3: ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.51 (m, 2 H), 7.47-7.40 (m, 2 H), 7.24-7.17 (m, 2 H), 6.87-6.79 (m, 2 H), 3.79 (s, 3 H).

3-Phenyl-4-vinylsydnone (2l)

This sydnone was prepared from sydnone 2a and vinyl bromide as a brown solid (40% yield) following Protocol 3: ¹H NMR (300 MHz, CDCl₃) δ 7.79-7.60 (m, 3 H), 7.59-7.50 (m, 2 H), 6.40-6.16 (m, 2 H), 5.41 (d, J = 10.6 Hz, 1 H).

4-(4-Acetylphenyl)-3-phenylsydnone (2m)

This sydnone was prepared from sydnone 2a and 4-bromoacetophenone as a yellow solid (30% yield) following Protocol 3: ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J = 7.7 Hz, 2 H), 7.76-7.56 (m, 3 H), 7.54-7.44 (m, 2 H), 7.43-7.33 (m, 2 H), 2.54 (s, 3 H).

4-(4-Methoxyphenyl)-3-phenylsydnone (2n)

This sydnone was prepared from sydnone 2a and 4-iodoanisole as a yellow solid (46% yield) following Protocol 3: ¹H NMR (400 MHz, CDCl₃) δ 7.66 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.2 Hz, 2 H), 7.48 (d, J = 7.6 Hz, 2 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 3.78 (s, 3 H).

3,4-Bis(4-chlorophenyl)sydnone (2p)

This sydnone was prepared from sydnone 2b and 4-bromochlorobenzene as a brown solid (44% yield) following Protocol 3: ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.55 (m, 2 H), 7.47-7.42 (m, 2 H), 7.31-7.27 (m, 2 H), 7.24 7.20 (m, 2 H).

3-(4-Chlorophenyl)-4-(2-thiophenyl)sydnone (2q)

This sydnone was prepared from sydnone 2b and 2-iodothiophene as a brown solid (50% yield) following Protocol 3: ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 3.7 Hz, 1 H), 7.28 (d, J = 5.0 Hz, 1 H), 7.02 (t, J = 4.5 Hz, 1 H).

3-(4-Chlorophenyl)-4-(2-pyridyl)sydnone (2r)

This sydnone was prepared from sydnone 2b and 2-bromopyridine as a brown solid (60% yield) following Protocol 3: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 4.6 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.75 (t, J = 7.8 Hz, 1 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H), 7.13 (dd, J = 7.4, 4.9 Hz, 1 H).

3-(4-Chlorophenyl)-4-(phenylethynyl)sydnone (2s)¹⁴

A solution of 79 mg of sydnone 2b (0.4 mmol) in 2 mL of toluene was charged with 4.5 mg of Pd(OAc)₂ (5 mol %), 6.8 mg of CuCl₂•2H₂O (10 mol %), and 186 mg of Ag₂O (2.0 equiv), and then heated to 75 °C in an open flask. A solution of 88 μL of phenylacetylene (0.6 mmol) in 3 mL of toluene was added over 6 h using a syringe pump while the reaction was stirred open to the air. The reaction was allowed to stir for an additional 2 h after the addition, and then EtOAc and water were added. The layers were separated and the EtOAc was washed with brine, dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography (petroleum ether/EtOAc) to afford 82 mg of 2s as a yellow solid (69% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.87-7.81 (m, 2 H), 7.67-7.61 (m, 2 H), 7.44-7.31 (m, 5 H).

4-Iodo-3-phenylsydnone (2t)¹⁵

To a solution of 243 mg of sydnone 2a (1.5 mmol) in 2.5 mL of acetic acid was added 185 mg of NaOAc (2.25 mmol, 1.5 equiv.), followed by a solution of 366 mg of ICl (2.25 mmol, 1.5 equiv.) in 1.5 mL of acetic acid. The mixture was allowed to stir for 3 h, then quenched with water and the solid was collected by filtration. The cake was washed with drops of cold ethanol and dried under vacuum to afford 272 mg of product (63%) as a brown solid. This representative procedure for preparing functionalized sydnones is identified as Protocol 4: ¹H NMR (400 MHz, CDCl₃) δ 7.73 (t, J = 7.2 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 2 H), 7.60 (d, J = 7.6 Hz, 2 H).

3-(4-Bromophenyl)-4-iodosydnone (2u)

This sydnone was prepared from sydnone 2c as a brown solid (60% yield) following Protocol 4: mp 160-162 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H); LRMS (ESI) 367 (M+H); HRMS (ESI) calcd for C₈H₅BrIN₂O₂ (M+H) 366.8574, found 366.8574.

4-Acetyl-3-phenylsydnone (2v)¹⁶

To a solution of 0.81 g of sydnone 2a (5 mmol) in 5 mL of acetic anhydride was added 0.89 g of NBS (5 mmol). The mixture was allowed to stir for 4 h, poured into 20 mL of ice water, and extracted by EtOAc. The combined organic layers were washed with saturated NaHCO₃ solution, dried over Na₂SO₄, and evaporated under vacuum. The residue was purified by column chromatography (5:1 petroleum ether/EtOAc) to afford 529 mg of product (52% yield) as colorless crystals: ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 7.6 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.23 (d, J = 7.6 Hz, 1 H).

General procedure for the synthesis of 2H-indazoles

To an oven-dried 10 mL round-bottom flask equipped with a stir bar were added 140 mg of benzyne precursor (∼0.48 mmol, ∼1.2 equiv) and 0.4 mmol of sydnone. THF (4 mL) was added and the mixture was stirred until all solid dissolved. To this solution was added TBAF (∼160 mg of solid or ∼630 μL of 1M THF solution, ∼1.6 equiv) in one portion. The flask was sealed with a septum and a nitrogen balloon was attached. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was poured into saturated NaHCO₃ and extracted three times with EtOAc. The combined extracts were washed once with brine, dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography (petroleum ether/EtOAc) to afford the 2H-indazole.

2-Phenyl-2H-indazole (3aa)

Following the general procedure, this product was isolated as a white solid: mp 79-81 °C (lit³⁵ 81-82 °C); R_f = 0.45 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H), 7.92-7.89 (m, 2 H), 7.81 (dd, J = 8.8, 0.9 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.56-7.50 (m, 2 H), 7.43-7.38 (m, 1 H), 7.34 (ddd, J = 8.8, 6.6, 1.1 Hz, 1 H), 7.12 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.7, 140.5, 129.5, 127.9, 126.8, 122.7, 122.4, 120.9, 120.40, 120.37, 117.9; LRMS (ESI): 217 (M+Na), 195 (M+H); HRMS (ESI): calcd for C₁₃H₁₁N₂ (M+H) 195.0917, found 195.0916.

2-(4-Chlorophenyl)-2H-indazole (3ab)

White solid: mp 141-143 °C; R_f = 0.50 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1 H), 7.89-7.84 (m, 2 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.71 (d, J = 8.5 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.33 (ddd, J = 8.6, 6.6, 0.8 Hz, 1 H), 7.17-7.09 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.8, 138.9, 133.5, 129.7, 127.1, 122.8, 122.7, 122.0, 120.35, 122.30, 117.8; LRMS (ESI) 251 (M+Na), 229 (M+H); HRMS (ESI) calcd for C₁₃H₁₀ClN₂ (M+H) 229.0527, found 229.0525.

2-(4-Bromophenyl)-2H-indazole (3ac)

Yellow solid: mp 146-148 °C; R_f = 0.38 (5:1 petroleum ether/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H), 7.79-7.75 (m, 3 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 9.2 Hz, 2 H), 7.32 (dd, J = 7.6, 6.8 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 150.1, 139.7, 132.8, 127.3, 123.1, 122.9, 122.4, 121.6, 120.6, 120.4, 118.1; LRMS (ESI) 273 (M+H); HRMS (ESI) calcd for C₁₃H₁₀BrN₂ (M+H) 273.0022, found 273.0030.

2-(4-Tolyl)-2H-indazole (3ad)

White solid: mp 101-103 °C; R_f = 0.44 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 0.9 Hz, 1 H), 7.83-7.76 (m, 3 H), 7.71 (dt, J = 8.5, 1.0 Hz, 1 H), 7.38-7.29 (m, 3 H), 7.11 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H), 2.43 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.6, 138.3, 137.9, 130.1, 126.6, 122.7, 122.3, 120.8, 120.30, 120.28, 117.9, 21.0; LRMS (ESI) 231 (M+Na), 209 (M+H); HRMS (ESI) calcd for C₁₄H₁₃N₂ (M+H) 209.1073, found 209.1072.

2-(4-Methoxyphenyl)-2H-indazole (3ae)

Yellow solid: mp 130-132 °C; R_f = 0.25 (5:1 petroleum ether/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H), 7.79 (d, J = 8.8 Hz, 3 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.31 (dd, J = 7.6, 7.2 Hz, 1 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 159.4, 149.7, 134.3, 126.7, 122.8, 122.6, 122.4, 120.5, 120.4, 117.9, 114.8, 55.8; LRMS (ESI) 257 (M+Na), 225 (M+H); HRMS (ESI) calcd for C₁₄H₁₃N₂O (M+H) 225.1022, found 225.1026.

2-(3,4-Methylenedioxyphenyl)-2H-indazole (3af)

Pale white solid: mp 117-118 °C; R_f = 0.31 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1 H), 7.77 (dd, J = 8.8, 0.9 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 2.2 Hz, 1 H), 7.35-7.29 (m, 2 H), 7.11 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.07 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.1, 148.4, 147.3, 135.2, 126.7, 125.6, 122.3, 120.5, 120.2, 117.7, 114.4, 108.4, 103.1, 101.9; LRMS (ESI) 261 (M+Na), 239 (M+H); HRMS (ESI) calcd for C₁₄H₁₁O₂N₂ (M+H) 239.0815, found 239.0812.

2-Methyl-2H-indazole (3ah)

Yellow oil: R_f = 0.21 (2:1 petroleum ether/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 4.21 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.2, 126.0, 123.7, 122.3, 121.8, 120.1, 117.4, 40.5; LRMS (APCI) 133 (M+H); HRMS (APCI) calcd for C₈H₉N₂ (M+H) 133.0760, found 133.0762.

2-Benzyl-2H-indazole (3ai)

Yellow oil: R_f = 0.31 (5:1 petroleum ether/EtOAc); ¹H NMR (300 MHz, CDCl₃) δ 7.86 (s, 1 H), 7.73 (dd, J = 8.7, 0.9 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.34-7.30 (m, 3 H), 7.27-7.23 (m, 3 H), 7.06 (dd, J = 8.1, 7.5 Hz, 1 H), 5.57 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.0, 135.9, 129.1, 128.5, 128.1, 126.2, 123.0, 122.2, 121.9, 120.3, 117.7, 57.6; LRMS (APCI) 209 (M+H); HRMS (APCI) calcd for C₁₄H₁₃N₂ (M+H) 209.1073, found 209.1078.

2,3-Dihydro-1H-pyrrolo[1,2-b]indazole (3aj)

Off-white solid: mp 99-100 °C; R_f = 0.31 (1:1 CH₂Cl₂/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 8.3 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 4.42 (t, J = 7.3 Hz, 2 H), 3.18 (t, J = 7.2 Hz, 2 H), 2.84-2.63 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 153.5, 138.8, 125.5, 120.3, 119.8, 117.6, 116.1, 48.9, 25.7, 23.0; LRMS (ESI) 181 (M+Na), 159 (M+H); HRMS (ESI) calcd for C₁₀H₁₁N₂ (M+H) 159.0917, found 159.0915.

2-(4-Chlorophenyl)-3-isobutyl-2H-indazole (3ak)

Slightly orange solid: mp 77-79 °C; R_f = 0.47 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 7.72-7.68 (m, 1 H), 7.65 (dt, J = 8.5, 1.0 Hz, 1 H), 7.55-7.44 (m, 4 H), 7.33 (ddd, J = 8.8, 6.6, 1.1 Hz, 1 H), 7.08 (ddd, J = 8.5, 6.6, 0.8 Hz, 1 H), 2.91 (d, J = 7.4 Hz, 2 H), 2.04-1.89 (m, 1 H), 0.83 (d, J = 6.6 Hz, 6 H); ¹³C NMR (100 MHz, CDCl₃) δ 148.6, 138.7, 136.3, 134.8, 129.3, 127.6, 126.8, 121.5, 121.1, 120.4, 117.5, 34.1, 29.2, 22.5; LRMS (ESI) 307 (M+Na), 285 (M+H); HRMS (ESI) calcd for C₁₇H₁₈ClN₂ (M+H) 285.1153, found 285.1151.

2-Phenyl-3-vinyl-2H-indazole (3al)

Yellow gel: R_f = 0.18 (5:1 hexanes ether/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 8.7 Hz, 1 H), 7.64-7.48 (m, 5 H), 7.43-7.34 (m, 2 H), 7.23-7.15 (m, 1 H), 6.81 (dd, J = 17.8, 11.6 Hz, 1 H), 6.04 (dd, J = 17.8, 0.8 Hz, 1 H), 5.53 (dd, J = 11.6, 0.9 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 148.8, 139.6, 133.2, 129.1, 128.8, 126.7, 126.2, 124.9, 122.7, 120.6, 120.3, 118.0, 117.7; LRMS (EI) 220 (M), 219 (M-H); HRMS (EI) calcd for C₁₅H₁₂N₂ (M) 220.1000, found 220.0990.

3-(4-Acetylphenyl)-2-phenyl-2H-indazole (3am)

Yellow solid: mp 135-137 °C (lit¹⁸ 136-138 °C); R_f = 0.36 (2:1 hexanes/EtOAc); ¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, J = 8.1 Hz, 2 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.47-7.36 (m, 8 H), 7.18 (t, J = 7.6 Hz, 1 H), 2.61 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 197.3, 149.0, 139.9, 136.2, 134.4, 133.9, 129.6, 129.1, 128.6, 128.6, 127.1, 125.9, 123.2, 121.8, 120.0, 117.9, 26.6; LRMS (EI) 312 (M); HRMS (EI) calcd for C₂₁H₁₆N₂O (M) 312.1263, found 312.1262.

3-(4-Methoxyphenyl)-2-phenyl-2H-indazole (3an)

Yellow solid: mp 103-105 °C; R_f = 0.52 (2:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz, 1 H); 7.69 (d, J = 8.4 Hz, 1 H), 7.39 (d, J = 2.4 Hz, 2 H), 7.38-7.33 (m, 4 H), 7.27 (d, J = 8.8 Hz, 2 H), 7.12 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2 H); 3.82 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 159.7, 149.0, 140.4, 135.5, 131.1, 129.1, 128.3, 127.1, 126.1, 122.4, 122.2, 121.7, 120.8, 117.8, 114.4, 55.4; LRMS (EI) 300 (M); HRMS (EI) calcd for C₂₀H₁₆N₂O (M) 300.1263, found 300.1272.

2-(4-Chlorophenyl)-3-(4-methoxyphenyl)-2H-indazole (3ao)

Slightly brown solid: mp 122-124 °C; R_f = 0.39 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.42-7.33 (m, 5 H), 7.30-7.26 (m, 2 H), 7.13 (ddd, J = 8.4, 6.6, 0.7 Hz, 1 H), 6.99-6.91 (m, 2 H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 159.7, 149.0, 138.8, 135.4, 133.9, 130.9, 129.2, 127.2, 127.1, 122.4, 121.8, 121.7, 120.6, 117.6, 114.4, 55.3; LRMS (ESI) 357 (M+Na), 335 (M+H); HRMS (ESI) calcd for C₂₀H₁₆ClN₂O (M+H) 335.0946, found 335.0942.

2,3-Bis(4-chlorophenyl)-2H-indazole (3ap)

Pale white solid: mp 126-129 °C; R_f = 0.52 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.43-7.35 (m, 7 H), 7.32-7.27 (m, 2 H), 7.17 (ddd, J = 8.5, 6.6, 0.7 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.1, 138.4, 134.7, 134.3, 134.1, 130.8, 129.35, 129.29, 128.0, 127.4, 127.1, 123.1, 121.8, 120.1, 117.8; LRMS (ESI) 361 (M+Na), 339 (M+H); HRMS (ESI) calcd for C₁₉H₁₃Cl₂N₂ (M+H) 339.0450, found 339.0448.

2-(4-Chlorophenyl)-3-(2-thiophenyl)-2H-indazole (3aq)

Yellow solid: mp 99-101 °C; R_f = 0.49 (6:1 petroleum ether/EtOAc).³⁶ The product spot overlapped with a highly fluorescent spot that immediately follows the product spot. Performing column chromatography with 8:1:0.4 petroleum ether/CH₂Cl₂/EtOAc offers some help in separation and purification of the desired product: ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.5 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.49-7.35 (m, 6 H), 7.19 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H), 7.10 (dd, J = 5.1, 3.6 Hz, 1 H), 7.03 (dd, J = 3.6, 1.1 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 148.9, 138.4, 134.7, 129.9, 129.6, 129.3, 128.4, 127.69, 127.65, 127.5, 127.3, 123.0, 121.9, 120.5, 117.7; LRMS (ESI) 333 (M+Na), 311 (M+H); HRMS (ESI) calcd for C₁₇H₁₂ClSN₂ (M+H) 311.0404, found 311.0404. The contaminant (the fluorescent spot) shows a series of non-overlapped signals as follows: 7.87 (d, J = 8.5 Hz), 7.50 (apparent t, J = 9.0 Hz), 7.13 (d, J = 3.8 Hz), 6.88 (d, J = 3.8 Hz).

2-(4-Chlorophenyl)-3-(2-pyridyl)-2H-indazole (3ar)

Slightly brown solid: mp 137-139 °C; R_f = 0.25 (6:1 petroleum ether/EtOAc);^{36 1}H NMR (400 MHz, CDCl₃) δ 8.71-8.67 (m, 1 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.71 (td, J = 7.8, 1.8 Hz, 1 H), 7.44-7.36 (m, 5 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.29-7.24 (m, 1 H), 7.21 (ddd, J = 8.5, 6.6, 0.7 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 150.2, 149.2, 149.1, 139.1, 136.5, 134.3, 134.1, 129.2, 127.3, 127.1, 124.6, 123.6, 122.6, 122.3, 120.7, 117.8; LRMS (ESI) 328 (M+Na), 306 (M+H); HRMS (ESI) calcd for C₁₈H₁₃ClN₃ (M+H) 306.0793, found 306.0790.

2-(4-Chlorophenyl)-3-phenylethynyl-2H-indazole (3as)

Yellow solid: mp 141-144 °C; R_f = 0.50 (6:1 petroleum ether/EtOAc).³⁶ The product spot overlapped with some spots that have a long wavelength UV absorption. Performing column chromatography with 8:1:0.4 petroleum ether/CH₂Cl₂/EtOAc offers some help in separation and purification of the desired product. The impurities do not show more than minimum contamination by ¹H NMR spectroscopy: ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.95 (m, 2 H), 7.87-7.78 (m, 2 H), 7.58-7.49 (m, 4 H), 7.43-7.36 (m, 4 H), 7.25-7.21 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 148.7, 138.6, 134.3, 131.3, 129.19, 129.14, 128.6, 127.6, 125.6, 125.5, 123.5, 121.9, 120.2, 118.2, 100.7, 77.7 (one overlapped signal); LRMS (ESI) 329 (M+H); HRMS (ESI) calcd for C₂₁H₁₄ClN₂ (M+H) 329.0840, found 329.0837.

3-Iodo-2-phenyl-2H-indazole (3at)

Off-white solid: mp 104-105 °C; R_f = 0.42 (5:1 petroleum ether/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 2 H), 7.50 (m, 4 H), 7.36 (dd, J = 7.6, 6.8 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 150.1, 140.6, 129.4, 129.1, 128.4, 127.7, 126.8, 123.3, 121.2, 118.4, 76.2; LRMS (ESI) 321 (M+H); HRMS (ESI) calcd for C₁₃H₁₀IN₂ (M+H) 320.9883, found 320.9884.

2-(4-Bromophenyl)-3-iodo-2H-indazole (3au)

Yellow solid: mp 159-161 °C; R_f = 0.38 (5:1 petroleum ether/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.54 (d, J = 8.8 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.18 (t, J = 7.4 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 150.4, 139.6, 132.5, 132.4, 128.7, 128.4, 128.0, 123.6, 121.3, 118.5, 76.0; LRMS (ESI) 399 (M+H); HRMS (ESI) calcd for C₁₃H₉BrIN₂ (M+H) 398.8988, found 398.8988.

5,6-Dimethyl-2-phenyl-2H-indazole (3ba)

White solid: mp 133-135 °C; R_f = 0.24 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1 H), 7.87 (d, J = 7.8 Hz, 2 H), 7.56 (s, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.40 (s, 2 H), 7.36 (t, J = 7.4 Hz, 1 H), 2.39 (s, 3 H), 2.34 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.6, 140.5, 137.2, 132.3, 129.4, 127.3, 121.8, 120.5, 119.0, 118.6, 116.5, 21.1, 20.5; LRMS (EI) 222 (M), 207 (M-Me); HRMS (EI) calcd for C₁₅H₁₄N₂ (M) 222.1157, found 222.1155.

5,6-Dimethoxy-2-phenyl-2H-indazole (3ca)

White solid: mp 147-148 °C (lit³⁷ 149-150 °C); R_f = 0.26 (2:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1 H), 7.84 (d, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.9 Hz, 2 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.06 (s, 1 H), 6.89 (s, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 152.0, 148.4, 146.6, 140.5, 129.5, 127.0, 120.0, 119.1, 117.4, 96.9, 95.8, 55.9; LRMS (EI) 254 (M); HRMS (EI) calcd for C₁₅H₁₄N₂O₂ (M) 254.1055, found 254.1059.

5-Methyl-2-phenyl-2H-indazole and 6-methyl-2-phenyl-2H-indazole (3da + 3da')

Slightly yellow solid: R_f = 0.26 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, mixture of isomers, two sets of signals) δ 8.32 (s, 1 H), 8.27 (s, 1 H), 7.89 (s, 2 H), 7.87 (s, 2 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.53-7.47 (m, 4 H), 7.55 (s, 1 H), 7.43 (s, 1 H), 7.41-7.34 (m, 2 H), 7.17 (d, J = 8.6 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 2.48 (s, 3 H), 2.43 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃, mixture of isomers) δ 150.3, 148.7, 140.5, 136.7, 131.7, 129.8, 129.4, 127.6, 125.4, 123.0, 121.1, 120.73, 120.70, 120.1, 119.8, 119.4, 118.3, 117.5, 116.1, 22.3, 21.8 (some overlap); LRMS (EI) 208 (M); HRMS (EI) calcd for C₁₄H₁₂N₂ (M) 208.1000, found 208.1003.

5-Methoxy-2-phenyl-2H-indazole and 6-Methoxy-2-phenyl-2H-indazole (3ea + 3ea')

Yellow solid: R_f = 0.25 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, mixture of isomers, two sets of signals) δ 8.27 (s, 1H), 8.22 (s, 0.8 H), 7.84 (d, J = 8.4 Hz, 3.6 H), 7.68 (d, J = 9.2 Hz, 0.8 H), 7.53 (d, J = 9.2 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 3.6 H), 7.36-7.32 (m, 1.8 H), 7.04-7.02 (m, 1.8 H), 6.86 (d, J = 2.0 Hz, 0.8 H), 6.80 (dd, J = 8.8, 1.6 Hz, 1 H), 3.87 (s, 3 H), 3.82 (s, 2.4 H); ¹³C NMR (100 MHz, CDCl₃, mixture of isomers) δ 159.5, 155.6, 151.0, 146.9, 140.7, 140.6, 129.6, 127.6, 127.5, 122.9, 122.2, 121.4, 120.7, 120.53, 120.50, 119.46, 119.41, 118.7, 118.0, 96.4, 94.7, 55.5, 55.4 (one overlapped signal); LRMS (ESI) 225 (M+H); HRMS (ESI) calcd for C₁₄H₁₃N₂O (M+H) 225.1022, found 225.1022.

4-Methyl-2-phenyl-2H-indazole and 7-methyl-2-phenyl-2H-indazole (3fa + 3fa')

Yellow oil: R_f = 0.35 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, mixture of isomers, two sets of signals) δ 8.35 (s, 1 H), 8.32 (s, 0.7 H), 7.88(dd, J = 8.4, 2.0 Hz, 3.4 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.52-7.46 (m, 4.1 H), 7.37-7.34 (m, 1.7 H), 7.23-7.19 (m, 1 H), 7.07-6.98 (m, 1.4 H), 6.84 (d, J = 6.8 Hz, 1 H), 2.68 (s, 2.1 H), 2.54 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃, mixture of isomers) δ 150.3, 150.0, 140.8, 140.7, 130.7, 129.7, 128.2, 127.93, 127.89, 127.4, 125.8, 124.3, 122.9, 122.7, 121.7, 121.3, 121.1, 120.9, 119.7, 117.9, 115.4, 19.3, 17.3; LRMS (ESI) 209 (M+H); HRMS (ESI) calcd for C₁₄H₁₃N₂ (M+H) 209.1073, found 209.1078.

2-Phenyl-2H-benzo[g]indazole and 2-phenyl-2H-benzo[e]indazole (3ga + 3ga')

Yellow gel: R_f = 0.42 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, mixture of isomers, two sets of signals) δ 8.74 (d, J = 8.0 Hz, 1 H), 8.71 (s, 1 H), 8.33 (s, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.93 (t, J = 7.2 Hz, 4 H), 7.83 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 9.2 Hz, 1 H), 7.62 (m, 2 H), 7.52 (m, 8 H), 7.38 (m, 3 H); ¹³C NMR (100 MHz, CDCl₃, mixture of isomers) δ 148.9, 147.7, 140.7, 140.6, 132.9, 130.6, 129.72, 129.69, 129.3, 129.1, 128.6, 127.6, 127.5, 127.4, 127.2, 127.1, 126.9, 125.8, 125.6, 124.7, 123.6, 122.8, 121.2, 120.6, 120.5, 120.2, 120.0, 118.5, 117.9, 117.5; LRMS (ESI) 245 (M+H); HRMS (ESI) calcd for C₁₇H₁₃N₂ (M+H) 245.1073, found 245.1064.

4-Methoxy-2-phenyl-2H-indazole (3ia)

Following the general procedure, this product was isolated as a white gel by collecting the first spot: R_f = 0.24 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H), 7.89 (d, J = 8.1 Hz, 2 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.44-7.33 (m, 2 H), 7.31-7.18 (m, 1 H), 6.35 (d, J = 7.3 Hz, 1 H), 3.96 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 153.4, 151.2, 140.4, 129.5, 127.70, 127.65, 120.7, 119.0, 116.8, 110.3, 98.8, 55.2; LRMS (EI) 224 (M), 209 (M-Me); HRMS (EI) calcd for C₁₄H₁₂N₂O (M) 224.0950, found 224.0950. The 2D NMR spectra and the analysis are included in the SI.

7-Methoxy-2-phenyl-2H-indazole (3ia')

The second spot of the aforementioned column chromatography afforded a yellow gel: R_f = 0.12 (5:1 hexanes/EtOAc). This material was stirred with 1 mL of Ac₂O and 1 mL of pyridine at room temperature for 30 min. Then the volatiles were evaporated under a vacuum, and the product purified by column chromatography: ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H), 7.93 (d, J = 8.0 Hz, 2 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 7.02 (dd, J = 8.4, 0.8 Hz, 1 H), 6.58 (d, J = 7.2 Hz, 1 H), 4.04 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 150.6, 143.5, 140.5, 129.6, 128.0, 124.5, 123.3, 121.2, 120.8, 112.5, 103.3, 55.7; LRMS (ESI) 225 (M+H), 247 (M+Na), 471 (2M+Na); HRMS (ESI) calcd for C₁₄H₁₃N₂O (M+H) 225.1022, found 225.1024. This regioisomer matches the reported ¹H and ¹³C NMR spectral data.¹⁸

4-Methoxy-2-(4-methylphenyl)-2H-indazole (3id)

Following the general procedure, this product was isolated as a white gel by collecting the first spot: R_f = 0.30 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1 H), 7.76 (d, J = 7.6 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 2 H), 7.24-7.20 (m, 1 H), 6.34 (d, J = 7.2 Hz, 1 H), 3.94 (s, 3 H), 2.40 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 153.6, 151.3, 138.3, 137.9, 130.2, 127.7, 120.8, 119.1, 116.9, 110.4, 98.9, 55.4, 21.2; LRMS (ESI) 239 (M+H); HRMS (ESI) calcd for C₁₅H₁₅N₂O (M+H) 239.1179, found 239.1179.

7-Methoxy-2-(4-methylphenyl)-2H-indazole (3id')

The second spot of the aforementioned column chromatography afforded a yellow gel: R_f = 0.22 (5:1 hexanes/EtOAc). This material was stirred with 1 mL of Ac₂O and 1 mL of pyridine at room temperature for 30 min. Then the volatiles were evaporated under vacuum, and the product purified by column chromatography: ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.26 (t, J = 9.2 Hz, 3 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.57 (d, J = 7.6 Hz, 1 H), 4.03 (s, 3 H), 2.39 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 150.5, 143.3, 138.3, 137.9, 130.0, 124.4, 123.1, 121.0, 120.6, 112.4, 103.1, 55.6, 21.2; LRMS (ESI) 239 (M+H), 261 (M+Na); HRMS (ESI) calcd for C₁₅H₁₄N₂ONa (M+Na) 261.0998, found 261.0999.

Procedure for the Suzuki-Miyaura Coupling with Boronic Acids

To a 4 dram vial were added the starting material 3at (∼0.4 mmol), the boronic acid (1.5 equiv.), KOH (3.0 equiv.) and Pd(PPh₃)₄ (5 mol %) in 20 : 5 : 1 toluene/ethanol/H₂O (4 mL in total). The solution was vigorously stirred for 5 min at room temperature, flushed with argon and sealed, and then heated to 80 °C until TLC revealed complete conversion of the starting material. Upon cooling to room temperature, the resulting reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO₄, concentrated, and purified by column chromatography to afford the following product.

3-(3,4-Methylenedioxyphenyl)-2-phenyl-2H-indazole (4at)

Following the general procedure, this product was isolated as a brown solid: mp 154-156 °C; R_f = 0.31 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.45 (d, J = 6.8 Hz, 2 H), 7.42-7.33 (m, 4 H), 7.12 (dd, J = 8.0, 7.2 Hz, 1 H), 6.87-6.81 (m, 2 H), 6.78 (s, 1 H), 5.98 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 149.0, 148.1, 147.9, 140.2, 135.3, 129.2, 128.4, 127.2, 126.1, 124.0, 123.5, 122.5, 121.8, 120.6, 117.8, 110.0, 108.9, 101.5; LRMS (ESI) 315 (M+H); HRMS (ESI) calcd for C₂₀H₁₅N₂O₂ (M+H) 315.1128, found 315.1125.

Procedure for the Sonogashira Coupling with a Terminal Alkyne

To a 4 dram vial was added the starting material 3at (∼0.4 mmol), the alkyne (1.2 equiv.), PdCl₂(PPh₃)₂ (3 mol %), CuI (3 mol %), DMF (1.5 mL) and Et₂NH (1.5 mL). The solution was stirred at room temperature, flushed with argon and sealed, and then heated to 60 °C until TLC analysis revealed complete conversion of the starting material. The solution was allowed to cool and diluted with EtOAc. The combined organic layers were dried over MgSO₄, concentrated, and purified by column chromatography to afford the following product.

3-(3-Methoxyprop-1-ynyl)-2-phenyl-2H-indazole (5at)

Yellow oil: R_f = 0.25 (5:1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 7.6 Hz, 2 H), 7.78 (dd, J = 15.6, 8.8 Hz, 2 H), 7.53 (t, J = 7.8 Hz, 2 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.20 (t, J = 7.4 Hz, 1 H), 4.41 (s, 2 H), 3.43 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 148.7, 140.2, 129.2, 128.9, 127.5, 126.1, 124.7, 123.6, 120.2, 118.5, 117.7, 96.7, 75.4, 60.7, 58.0; LRMS (ESI) 263 (M+H); HRMS (ESI) calcd for C₁₇H₁₅N₂O (M+H) 263.1179, found 263.1180.