From N–H Nitration to Controllable Aromatic Mononitration and Dinitration—The Discovery of a Versatile and Powerful N-Nitropyrazole Nitrating Reagent

Abstract

Nitroaromatics are tremendously valuable organic compounds with a long history of being used as pharmaceuticals, agrochemicals, and explosives as well as vital intermediates to a wide variety of chemicals. Consequently, the exploration of aromatic nitration has become an important endeavor in both academia and industry. Herein, we report the identification of a powerful nitrating reagent, 5-methyl-1,3-dinitro-1H-pyrazole, from the N-nitro-type reagent library constructed using a practical N–H nitration method. This nitrating reagent behaves as a controllable source of the nitronium ion, enabling mild and scalable nitration of a broad range of (hetero)arenes with good functional group tolerance. Of note, our nitration method could be controlled by manipulating the reaction conditions to furnish mononitrated or dinitrated product selectively. The value of this method in medicinal chemistry has been well established by its efficient late-stage C–H nitration of complex biorelevant molecules. Density functional theory (DFT) calculations and preliminary mechanistic studies reveal that the powerfulness and versatility of this nitrating reagent are due to the synergistic “nitro effect” and “methyl effect”.

Nitroaromatics are tremendously valuable organic compounds. On the one side, nitroaromatics have proven to possess diversified practical values, with a long history of being used as pharmaceuticals,^1a,1b agrochemicals,^1c explosives,^1d and other function materials.^1e,1f On the other side, the nitro group is regarded as one of the most versatile functional groups for transformation,^2a which enables nitroarenes the vital precursors to a wide variety of chemicals, including nitrosoarenes,^2b anilines,^2c−^2e aromatic azo compounds,^1e biaryls,^2f,2g heterocycles,^2h−^2j etc. As a result, the exploration of aromatic nitration has been a significant endeavor in both academia and industry, culminating in the development of several impactful nitration strategies (Figure 1A).³ The most influential and widely used nitration strategy in both laboratory and industry is electrophilic aromatic substitution (S_EAr), with the “mixed acids” protocol as the representative one, which requires the use of concentrated nitric acid and another assisting reagent (e.g., H₂SO₄, Tf₂O or Ac₂O) to generate the reactive nitronium ion ([NO₂⁺]).^3a Other strategies include transition metal-catalyzed cross coupling⁴ or directed C–H activation⁵ with nitrites or nitrates, ipso-nitration of prefunctionalized arenes⁶ (e.g., aryl boronic acids, aryl carboxylic acids, and aryl metal species), oxidation of aryl azides⁷ or anilines,⁸ as well as enzymatic,⁹ electrochemical,¹⁰ and photochemical nitrations.¹¹ Despite their effectiveness, these methods suffer from certain limitations, including (a) poor functional group tolerance due to harsh reaction conditions (e.g., strong acids, strong oxidants or high temperature), (b) the requirement of prefunctionalization or directing group, and (c) adverse environmental impact. Path-pointing efforts by the groups of Kauffman,^12a Coburn,^12b Olah,^12c,12d Pearson,^12e Katayev,^12f and recently by Wang¹¹ et al. paved another attractive way for arene nitration—using a N-nitro-type reagent, such as N-nitrolactams, N-nitropyridine salts, N-nitropyrazole, N-nitrosaccharin, and N-nitroimidazole (Figure 1B). However, there are two challenges associated with this approach. First is the lack of practical access to these N-nitro-type reagents, which currently have to be prepared by N–H nitration with either in situ-generated [NO₂⁺] under harsh conditions^11,12a−12f or a [^•NO₂] radical under electrocatalysis.¹³ Second, most of the reported N-nitro-type reagents displayed unsatisfied nitrating ability and a narrow substrate scope.^11,12a-12e Therefore, a prerequisite to an efficient aromatic nitration using N-nitro-type reagents could be the identification of a new generation of reagents with good reactivity, which we envisaged could be realized through screening a diversified reagent library specially designed and prepared (Figure 1C). Herein, we report our work on both the identification of a powerful nitrating reagent 5-methyl-1,3-dinitro-1H-pyrazole and the nitration of a broad range of aromatics under mild conditions using this bench-stable reagent (Figure 1D).

Figure 1.

Aromatics nitrations. TM: transition metal, DG: directing group, TBN: tert-butyl nitrite, CAN: ceric ammonium nitrate, and LA: Lewis acid.

Our efforts started from developing a general protocol for N–H nitration for the establishment of a diversified N-nitro reagent library. After rational reaction design and careful preliminary studies, we observed that the combination of tert-butyl nitrite (TBN)¹⁴ and an additional oxidant ceric ammonium nitrate (CAN)¹⁵ could promote N–H nitration of pyrazoles (for details, see Table S1). Further optimization of this attractive N–H nitration approach (for details, see Tables S1–S4) led to the following optimal nitration conditions: running the reaction in MeCN at 100 °C, with TBN as a source of nitro and CAN and O₂ as oxidants. Gratifyingly, as shown in Table 1A, the N–H nitration of a variety of substituted pyrazoles proceeded smoothly under the above reaction conditions, furnishing the desired products 2a–s in 38–95% yields on a 3.0 mmol scale. Pyrazole substrates with various substitutions were tolerated, including halides (2c–f), cyano (2g), nitro (2h, 2i, 2o, 2p, and 2s), trifluoromethyl (2j), ester (2k, 2q, 2r), and even free amide (2l). The reaction of pyrazoles with C3 electron-donating substitution produced the N-nitration products (2m and 2n) together with the C4 overnitrated products (2m′ and 2n′). Besides pyrazoles, other N–H-containing heterocycles, such as pyrrolidinone (1t), oxazolidin-2-one (1u), and benzotriazoles (1v–x) were also suitable substrates for nitration. Interestingly, the N–H nitration of substituted benzotriazoles afforded products as an inseparable mixture of regioisomers in good yields (2w and 2x). Therefore, by following this N–H nitration protocol and using inexpensive starting materials, we quickly established a N-nitro reagent library with 28 members, laying the foundation for the discovery of a new generation of nitrating reagents.

Table 1. Establishment of N-Nitro-Type Reagent Library and Nitrating Activity Evaluation^a.

^aAll reactions were performed on a 3.0 mmol scale unless otherwise noted. Isolated yields were reported.

^b2.0 equiv TBN.

^c1.0 mmol.

^dAll reactions were performed on a 0.2 mmol scale and 1.2 equiv of 2 was applied. GC yields with biphenyl as an internal standard.

We then evaluated the nitrating ability of these reagents toward the model substrate naphthalene (3a) (Table 1B). The reaction was performed in MeCN at 80 °C, with Cu(OTf)₂ as a Lewis acid catalyst.^12d,16 During the systematic screening of these nitrating reagents, an intriguing substituent effect on their nitrating ability was observed. For instance, N-nitro pyrazoles with electron-donating (2a, 2b) or weak electron-withdrawing substituents (2e, 2f) afforded α-nitrated product 1-nitronaphthalene (4a) in 9–14% yields, with the exception of 2d that furnished 4a in a 35% yield. In contrast, N-nitro pyrazoles with a strong electron-withdrawing substitution (2g, 2k) possessed significantly enhanced nitrating reactivity, and the corresponding yields of 4a increased to 30–64%. Notably, the nitrating reactivity could be further tuned by additional substitution on pyrazole. For instance, 2o and 2p derived from 2i with a C5 alkyl substitution showed much higher reactivity than 2i. However, 2r and 2s, derived from 2k and 2h, respectively, showed much lower reactivity. Thus, 2o was identified as the optimal nitrating reagent in the model reaction, affording 4a in an 89% yield. The structure of 2o has been unambiguously confirmed by X-ray crystallographic analysis (CCDC 2108423). To probe the safety of reagent 2o, its mechanical sensitivity were investigated by both computational and experimental methods.¹⁷ The calculated h50 value is 56.2 cm, which corresponds to an impact energy of 13.8 J from a 2.5 kg drop weight. The experimentally determined impact sensitivity and friction sensitivity are 13.2 J and 40–42 N, respectively. Therefore, 2o has a medium sensitivity. Further characterizations by thermal gravimetric analysis and differential scanning calorimetry (TGA–DSC) revealed 2o to be stable until 148 °C, whereby an exothermic event accompanied by a 9.9% mass loss was observed (for details, see Figure S1).¹⁸ It is worth mentioning that the molecular weight of 2o is small (M_w = 172.1), which means the nitration protocol based on 2o will have better atom economy than most of the previous strategies. Further optimization of reaction conditions was conducted to make 2o as a versatile nitrating reagent not only for the activated electron-rich aromatics but also for the challenging deactivated electron-deficient substrates (for details, see Tables S5–S14). For electron-rich aromatics, inexpensive commercial reagent Yb(OTf)₃ was identified as the optimal catalyst, and the optimized conditions were as follows: Yb(OTf)₃ (10 mol %) and 2o (1.5 equiv) in MeCN (0.2 M) at 80 °C (standard conditions I, Table S8). In addition, other Lewis acid (e.g., BF₃·Et₂O) and strong protic acid (e.g., CF₃SO₃H) were also suitable catalysts for the nitration of electron-rich aromatics, albeit with inferior efficiency comparing to Yb(OTf)₃ (for details, see Table S7). For deactivated aromatics, inexpensive reagents In(OTf)₃ and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)¹⁹ were identified as the optimal catalyst and solvent, respectively, and the optimized conditions were as follows: In(OTf)₃ (20 mol %) and 2o (2.0 equiv) in HFIP (0.5 M) at 80 °C (standard conditions II, Table S14).

With the optimal reaction conditions in hand, we then started to explore the substrate scope of this nitration method. As revealed in Table 2A, electron-rich aromatics, e.g., aryl ethers (3b, 3c), substituted anilides (3p–x), and phenols (3y–dd), could be smoothly nitrated by 2o under standard conditions I to afford the desired mononitrated products (4b, 4c, 4q–dd) in 47–99% yields. Benzene and other electron-rich aromatics should be nitrated under standard conditions II to get satisfied yields (58–97%). Interestingly, nitration of substituted phenols with an electron-withdrawing group, e.g., trifluoromethyl (4aa), ester (4bb), or nitro (4cc–dd), also proceeded well, affording the desired products in 50–71% yields. Arenes with electron-withdrawing substitutions (3rr–ss) were also suitable substrates under standard conditions II affording the corresponding nitrated products in 31–99% yields (Table 2B). Moreover, 2o was also a viable reagent for the nitration of various heteroaromatics and even alkenes (Table 2C). For example, benzo[d][1,3]dioxole (3tt), 2,3-dihydrobenzo[b][1,4]dioxine (3uu), substituted thiophenes (3vv–ww), benzothiophene (3xx), benzofuran (3yy), DNA base (uracil) analogue (3zz), and even 1,1-diphenylethylene (3zz′) reacted with 2o smoothly to afford the corresponding nitrated products in 46–84% yields. Notably, owing to the mild reaction conditions, the nitration proceeded with good chemoselectivity, and a broad array of functional groups were tolerated, including alkoxy (4b, 4c, 4e and 4ee), ((trifluoromethyl)sulfonyl)oxy (4d), sulfide (4f), halides (4h–k, 4p–s, 4y, 4z and 4ee), alkyl (4l–o), protected amino (4p–x), free phenol (4y–dd), ester (4n, 4bb and 4ss), trifluoromethyl (4aa), nitro (4cc–dd), and carbonyl (4qq–ss). Importantly, the regioselectivity of nitration was predictable. For monosubstituted electron-rich arenes, a mixture of p- and o-nitrated products were usually formed in an equal amount or with the former in a slight excess. However, for 3d, 3e and 3h, the para-nitrated product was isolated as the dominant or sole one (4d, 4e and 4h), which was probably owing to the steric and induction effects of the substitution. For most deactivated arenes with an extra p- or o-substitution, nitration took place predominantly or solely at the less sterically hindered meta-position (4gg–oo and 4qq–rr). However, in the cases of nitration of 1,2-dimethoxy-4-nitrobenzene (3pp) and 3,4-dimethoxybenzaldehyde (3ss), the o-nitrated products (4pp and 4ss) were isolated as the sole products, respectively, which was in stark contrast to 3oo and 3rr. Interestingly, for methyl benzoate (3ff), a substantial o-nitrated product was also formed besides the major m-nitrated product. Other salient features of this nitration method were scalability and recyclability in terms of the pyrazole moiety of 2o. For example, scale-up nitration of substrates 3a (7.0 mmol), benzene 3g (15.0 mmol), and 3ii (6.0 mmol) was successfully achieved to produce the corresponding nitration products 4a (1.18 g, 97%), 4g (1.70 g, 92%) and 4ii (1.03 g, 86%), respectively. It is worth mentioning that the denitro product of 2o (i.e., the pyrazole 1o) could be recovered in 78–94% yields. The scalability and recyclability of this nitration protocol make it attractive to chemists both in laboratory and in industry.

Table 2. Mononitration of (Hetero)arenes with 2o^a,b.

^aStandard conditions I: 3 (1.0 equiv), 2o (1.2–1.5 equiv), Yb(OTf)₃ (10 mol %), MeCN (0.2 M), and 80 °C. Standard conditions II: 3 (1.0 equiv), 2o (2.0 equiv), In(OTf)₃ (20 mol %), HFIP (0.5 M), and 80 °C.

^bAll reactions were performed on a 0.2 mmol scale unless otherwise noted. Isolated yields were reported. The minor regioisomeric position is labeled.

^cGram scale.

^d1.2 equiv of 2o.

^eThe deiodinative nitration product 1-methoxy-2,4-dinitrobenzene (4ee′) was also isolated in a 24% yield.

^fThe deformylative nitration product 4ee′ was also isolated in a 15% yield.

^gIn(OTf)₃ (10 mol %), 2o (1.5 equiv), MeCN (0.2 M), and 100 °C.

Polynitrated arenes are well-known for their application in high energy materials and other function materials. Nevertheless, their preparation is a formidable challenge since the introduction of the first nitro group into the aromatic motif will dramatically decelerate further nitrations.²⁰ Currently, these special chemicals are predominantly prepared through multiple separate nitration steps involving the use of extremely aggressive “mixed acids”.^20,21 Therefore, general mild methods are in urgent need for the synthesis of polynitrated arenes.^21c While probing the scope of nitration by 2o, we noticed that the nitration of anisole (3b) under standard conditions II provided the intriguing o,p-dinitrated product 5a in a 40% yield. Encouraged by this exciting finding, we aimed at developing an efficient dinitration protocol based on 2o. To our delight, the yield of dinitration was satisfyingly improved to 82% when 3.0 equiv of 2o was applied, which was set as the standard protocol for dinitration (standard conditions III). Gratifyingly, as revealed in Table 3, various electron-rich aromatics were suitable substrates for dinitration under standard conditions III, including monosubstituted anisoles (5b–i), veratrole derivatives (5j–p), polysubstituted aryl ethers (5q–t) and sulfonamide (5u). The regioselectivity of this dinitration protocol was excellent and predictable. For substituted anisoles (5b–i) and polysubstituted aryl ethers (5q–t), dinitration took place at the para- and (less-hindered) ortho-positions of the alkoxy group, with the exception of 3-methyl anisole, which generated three separable regioisomers: the major o,p-dinitrated products (5g: 40% and 5g′: 19%) and the minor o,o′-dinitrated product (5g″: 15%). Different from the substituted anisoles, dinitration of veratrole derivatives (5j–p) exclusively occured at the vicinal para-positions of the two alkoxy groups in excellent yields (79–99%). It was worth noting that this dinitration protocol was also scalable as demonstrated by a 5.0 mmol scale dinitration of 1,2-diethoxybenzene, which afforded 1.04 g of product 5k (86% yield) alongside 84% recovery of 1o. The structure of 5k was unambiguously assigned by X-ray crystallographic analysis (CCDC 2105485). Besides our general dinitration protocol, three interesting indirect dinitration reactions were also discovered, including decarboxylative ipso-nitration^22a (3bb′ to 4dd), deformylative ipso-nitration^22b (3ss to 5j), and deiodinative ipso-nitration^22c (3ee to 5a) (Table 3B). Such indirect dinitration methods not only supplemented our dinitration toolbox but also showcased the tunability of the nitration chemistry based on 2o.

Table 3. Dinitration of Arenes with 2o^a,b.

^aStandard conditions III: 3 (1.0 equiv), 2o (3.0 equiv), In(OTf)₃ (20 mol %), HFIP (0.5 M), and 80 °C.

^bAll reactions were performed on a 0.2 mmol scale. Isolated yields were reported.

^c4.0 equiv of 2o was used.

^d5.0 mmol scale.

^eThe mononitrated product 1-bromo-3-methoxy-2-methyl-4-nitrobenzene (5q′) was also formed in a 36% yield.

^f2.0 equiv of 2o was used.

The value of our aromatic nitration method in medicinal chemistry research was well established by its efficient late-stage C–H nitration of a series of complex biorelevant molecules (Table 4). Various drug analogues, including fenclorim (6a), clofibrate (6b), fenofibrate (6c), isoxepac (6d), procymidone (6e), veratricaldehyde (6f), nitrofen (6g), nimesulide (6h), and dicamba (6i) underwent nitration smoothly, affording the mononitrated products 7a–i in moderate to good yields (51–99%). In all of these cases, excellent regioselectivity was observed, presumably corresponding to positions of high electron density and less steric hindrance of the aromatic motifs. For example, the nitration of 6h took place exclusively on the more electron-rich arene motif as revealed by X-ray crystallographic analysis (7h, CCDC 2106743). Alternatively, without an especially electron-rich π-system present, competitive nitrations of the remaining aromatic sites could be observed. Not surprisingly, nitration of ibuprofen (6j) and benzbromarone (6k) under conditions II resulted in mononitration at multiple aromatic positions. In addition, subjection of triclosan (6l), flurbiprofen (6m), and gemfibrozil (6n) to our protocol (conditions II) similarly resulted in promiscuous mononitrated and dinitrated products, which were readily separated by column chromatography. Nevertheless, when 6n was subjected to conditions III, only the o,p-dinitrated product 7n′ was obtained in a 73% yield, which showed the potential of tunability of our nitration method. In the context of drug discovery, the introduction of a nitro group into a biorelevant molecule usually alters its physicochemical properties,^1a,1b,23 including bioreduction potential (prodrugs), pK_a value, the hydrophobicity, and steric size. Additionally, the incorporated nitro group can also serve as a useful functional handle for further investigation. Therefore, a facile access to these nitrated derivatives through a mild late-stage nitration bears the potential for uncovering new biological activities and functions rapidly.²⁴

Table 4. Late-Stage Nitration of Biorelevant Molecules and Drug Analogues^a.

^aAll reactions were performed on a 0.2 mmol scale. Isolated yields were reported.

To gain insights into the structure–activity relationship (SAR) of this new series of nitration reagents, preliminary mechanistic studies were conducted (Figure 2). First, we performed density functional theory (DFT) calculations to investigate the dissociation free energy of the N–NO₂ bonds of nitrating reagents 2a, 2i, and 2o, and the following three different dissociation approaches were taken into account: the homolytic cleavage (ΔG_Homo), heterolytic cleavage (ΔG_Het), and Cu(OTf)₂-assisted heterolytic cleavage (ΔG_Het(Cu)) (Figure 2A). The computational results indicated that neither homolytic cleavage nor heterolytic cleavage of the N–NO₂ bond was thermodynamically favorable for the nitration process. In stark contrast, the calculated ΔG_Het(Cu) values of 2a, 2i, and 2o were in the range of 27.7–44.1 kcal/mol, which were much lower compared to the corresponding ΔG_Het. Such dramatic Gibbs free energy decrease (>24 kcal/mol) indicated the heterolytic cleavage of the N–NO₂ bond was significantly facilitated by Cu(OTf)₂. Impressively, the calculated ΔG_Het(Cu) could also well explain the observed “substituent effects” on nitrating activity shown in Table 1B. For instance, the introduction of a nitro group into 2a led to an over 15 kcal/mol decrease of ΔG_Het(Cu) for 2i and 2o, which was tentatively named the “nitro effect”. An additional methyl substitution to 2i led to a further 0.5 kcal/mol decrease of ΔG_Het(Cu) for 2o, which was tentatively named the “methyl effect”. The “nitro effect” could be rationalized on the ground that the 3-NO₂ group of 2i and 2o would stabilize the generated anion and promote the coordination with Cu(OTf)₂ after the heterolytic cleavage of the N–NO₂ bond. A plausible explanation for the “methyl effect” was the introduction of a 5-methyl substituent into the pyrazole nucleus that might impede the nitro group from achieving coplanarity with the pyrazole ring and reduce the ratio of the double-bond character of the N–NO₂ bond in resonance structures, thus weakening this N–NO₂ bond in 2o. Indeed, the X-ray crystallographic analysis of 2o (CCDC 2108423) shows that the N–NO₂ bond length (1.435 Å) (Table S18) was considerably longer than in 2a (1.399 Å)²⁵ (Figure 2A). In addition, 2p, the methylene congener of 2o, exhibited equally excellent nitrating reactivity as 2o (Table 1B). Therefore, the X-ray structural information and the case of 2p strongly supported our explanation for both the “methyl effect” and the “nitro effect”. Moreover, the reaction profile studies also clearly demonstrated the superiority of reagent 2o over 2a and 2i in terms of nitration reactivity and efficiency (Figure 2B). Thus, the “nitro effect” and the “methyl effect” on tuning the nitration reactivity of the reagents 2a, 2i, and 2o are other striking examples of the SAR study that will surely inspire the development of next generation of nitration reagents.

Figure 2.

Preliminary mechanistic studies. (^aEnergies refer to Gibbs free energy (in kcal mol^–1) calculated using M06/6-311+G(d,p)-SDD/SMD(acetonitrile)//B3LYP-D3(BJ)/6-31G(d)-LANL2D. ^bAll reactions were performed on a 0.2 mmol scale. GC yields with tridecane as an internal standard).

Next, a competitive kinetic isotope effect (KIE) experiment between naphthalene (3a) and d₈-naphthalene was performed (Table S17), and the measured KIE was 0.88, indicating a secondary isotope effect, which is consistent with the previous studies by Olah²⁶ and Katayev.^12f Moreover, we performed a series of radical trapping control experiments, exemplified by performing the nitration of naphthalene (3a) with 2o in the presence of a radical scavenger (Table S16). As a result, no significant inhibition of nitration was observed. Therefore, both DFT calculations and the above control experiments favor an electrophilic aromatic nitration over a radical process.^3a,27 Moreover, probing the intriguing dinitration process, we carefully analyzed the selected data from Tables 2 and 3. As shown in Figure 2C, the reaction of anisole 3b with 2o under conditions I achieved the first nitration to afford mononitrated 4b as a mixture of 3nn and 3oo. Next, 3nn, 3oo, and 3pp further reacted with 2o under conditions II to achieve the second nitration, providing the dinitrated products 5a (4nn/4oo) and 5j (4pp) in excellent yields. These results supported the finding that the mild dinitration process actually went through a stepwise nitration mechanism. Currently, we are working on elucidating the mechanisms of the indirect dinitration reactions of Table 3B.

In conclusion, we have developed a practical N–H nitration method for the establishment of a diversified N-nitro-type reagent library from which a powerful nitration reagent 5-methyl-1,3-dinitro-1H-pyrazole (2o) was identified. 2o behaves as a controllable source of the nitronium ion with good atom economy, enabling mild and scalable nitration and dinitration protocols for a broad range of (hetero)arenes bearing various functional groups. Of note, the nitration is controllable through manipulating reaction conditions to furnish mononitrated or dinitrated product selectively. The value of this aromatic nitration method in medicinal chemistry research has been well established by its efficient late-stage C–H nitration of a series of complex biorelevant molecules. DFT calculations and preliminary mechanistic study reveal that the powerfulness and versatility of 2o are due to the synergistic “nitro effect” and “methyl effect”. Heterolytic cleavage of the N–NO₂ bond in 2o is greatly facilitated by a Lewis acid catalyst, thereby suggesting an electrophilic aromatic nitration mechanism.

Methods

General Procedure for the Synthesis of Nitrating Reagents

A 250 mL sealed tube equipped with a magnetic stir bar was charged under O₂ with 1 (3.0 mmol, 1.0 equiv), TBN (0.31 g, 3.0 mmol, 1.0 equiv), CAN (3.2 g, 6.0 mmol, 2.0 equiv) and MeCN (20.0 mL). The reaction mixture was then heated to 100 °C and stirred. After completion of the reaction (about 16 h, monitored by TLC), the mixture was cooled to room temperature (rt), filtered through a thin pad of celite eluting with ethyl acetate (EtOAc), and the combined filtrate was concentrated in vacuo. The residue was directly purified by column chromatography on silica gel (petroleum ether (PE)/EtOAc = 5:1) to give the desired product 2.

Standard Conditions I for the Nitration of Aromatics

A 10 mL oven-dried vial equipped with a magnetic stir bar was charged with 3 (0.2 mmol, 1.0 equiv), 2o (51.2 mg, 0.3 mmol, 1.5 equiv), Yb(OTf)₃ (12.4 mg, 0.02 mmol, 10 mol %) and dry MeCN (1.0 mL). The reaction mixture was then heated to 80 °C and stirred. After completion of the reaction (about 16 h, monitored by TLC), the mixture was cooled to rt, filtered through a thin pad of celite eluting with ethyl acetate (10 mL), and the combined filtrate was concentrated in vacuo. The residue was directly purified by column chromatography on silica gel (PE/EtOAc = 10:1) to give the desired product 4.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.2c00413.

• Experimental procedures, characterization data of products, calculation details, and X-ray crystallographic data for 2o, 5k, and 7h (PDF)

The authors declare no competing financial interest.