Tandem One-Pot Approach To Access 1,2,3-Triazole-fused

May 23, 2018 - Tandem One-Pot Approach To Access 1,2,3-Triazole-fused Isoindolines through Cu-Catalyzed 1,6-Conjugate Addition of Me3SiN3 to ...
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Note Cite This: J. Org. Chem. 2018, 83, 8596−8606

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Tandem One-Pot Approach To Access 1,2,3-Triazole-fused Isoindolines through Cu-Catalyzed 1,6-Conjugate Addition of Me3SiN3 to p‑Quinone Methides followed by Intramolecular Click Cycloaddition Abhijeet S. Jadhav, Yogesh A. Pankhade, and Ramasamy Vijaya Anand*

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Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, Knowledge City, Manauli (PO), S. A. S. Nagar, Mohali, Punjab 140306, India S Supporting Information *

ABSTRACT: A Cu-catalyzed one-pot approach has been developed for the synthesis of 1,2,3-triazole-fused tricyclic heterocycles. This tandem approach actually involves the 1,6conjugate addition of Me3SiN3 to o-alkynylated p-quinone methides followed by an intramolecular [3+2]-cycloaddition reaction. This protocol allowed us to access a wide range of 1,2,3-trazole-fused isoindoline derivatives in moderate to good yields.

O

Fused 1,2,3-triazoles are another set of compounds that possess a wide range of biological significance. For example, the 1,2,3-triazole derivatives 1 and 2 exhibit remarkable anticancer activities (Figure 1).11 The sugar-based fused 1,2,3-triazole

ver the past few decades, the chemistry of triazole-based heterocycles has gained significant attention due to their widespread applications in medicinal chemistry1 as well as in materials science.2 Particularly, a large number of 1,2,3-triazole derivatives possess interesting therapeutic activities and thus have been explored as potential drug candidates for the treatment of HIV, bacterial infection, cancer, etc.1 Owing to the large dipole moment and hydrogen bond acceptor capability, 1,2,3-triazoles could act as effective amide surrogates in biologically significant molecules.3 Moreover, these heterocycles also found a diverse range of applications in the industrial sector, such as agrochemical, dye, and polymer industries.4 The classical protocol to access 1,2,3-triazoles involves 1,3-dipolar cycloaddition of azides with alkynes, which is popularly described as the Huisgen reaction, under thermal conditions.5 However, low yields and poor regioselectivity (formation of 1,4- and 1,5-disubstituted products) were the main concerns, which rendered this method from practical applications. In order to overcome these issues, Sharpless6 and Meldal7 independently developed a Cu(I)-catalyzed [3+2]-cycloaddition of azides with alkynes (CuAAC), which is often referred as the “click reaction”, to access 1,4-disubstituted 1,2,3-triazoles under mild conditions. More importantly, the high regioselectivity outcome, i.e., the selective formation of 1,4disubstituted 1,2,3-triazoles over the 1,5-disubstituted products, made this reaction unique and popular in terms of synthetic applications.1,8 Apart from metal-catalyzed versions, in the recent past, several organocatalytic methods9 have been developed based on the Dimroth reaction, which essentially involves a base-mediated reaction between an active methylene compound with an organic azide, to access 1,2,3-triazoles.10 © 2018 American Chemical Society

Figure 1. Biologically active fused 1,2,3-triazole derivatives.

derivative 3 showed an interesting biological response toward α-glucosidase enzyme.12 The morpholine-derived triazole derivative 4 was found to have potential activity against Alzheimer disease (Figure 1).13 Generally, such fused 1,2,3-triazole derivatives could be accessed either through an intramolecular 1,3-dipolar cycloaddition between azides and alkynes (a, Scheme 1)14 or through a metal-catalyzed intramolecular C−C coupling Received: March 2, 2018 Published: May 23, 2018 8596

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

Note

The Journal of Organic Chemistry Scheme 1. Major Pathways To Access Fused 1,2,3-Triazole Derivatives

Table 1. Optimization Studies

between the 1,2,3-triazole unit and the halo-arene part (b, Scheme 1).15 Other miscellaneous protocols16 including organocatalytic methods (c, Scheme 1)9 have also been disclosed for the synthesis of fused 1,2,3-triazole derivatives. In recent years, there has been a growing interest in the area of p-quinone methides (p-QMs) chemistry as these compounds possess a unique 1,6-reactivity profile toward various nucleophiles.17 While exploring the p-QMs as 1,6-acceptors to prepare unsymmetrical diaryl- and triarylmethane derivatives,18 we thought of utilizing this chemistry to synthesize fused 1,2,3-triazole derivatives. Consequently, we have developed an unprecedented tandem one-pot approach to access 1,2,3-triazole-fused isoindolines through a Cu(I)catalyzed 1,6-conjugate addition of azides to o-alkynylated pQMs followed by intramolecular click cycloaddition, and the results are disclosed herein. The 2-alkynylated p-quinone methides were prepared as shown in Scheme 2. The optimization studies were performed

entry

catalyst

solvent

temp (°C)

time (h)

yield (%)

1 2 3b 4 5 6 7 8 9 10 11 12 13 14 15 16c 17d

CuI CuI CuI CuI Cu(OAc)2 CuSO4·H2O Cu(OTf)2 CuOTf·toluene AgSbF6 AgNTf2 PPh3PAuNTf2 PdCl2 CuOTf·toluene CuOTf·toluene CuOTf·toluene CuOTf·toluene CuOTf·toluene

DCE DCE DCE MeCN DCE DCE DCE DCE DCE DCE DCE DCE DCM toluene MeCN DCE DCE

rt 60 60 60 60 60 60 60 60 60 60 60 40 60 60 60 60

36 36 36 36 36 36 12 12 24 36 36 36 36 36 36 36 36

NR NR 15 70 trace 27 72 85 60 45 41 trace 30 65 76 65 NR

a

Reaction conditions: all reactions were carried out with 0.051 mmol 5a and 0.152 mmol Me3SiN3 in a solvent (1.5 mL). b11 mol % of 2,2′bipyridyl has been used as a ligand. c2 equiv of Me3SiN3 was used. d NaN3 was used instead of Me3SiN3. NR = no reaction; rt = room temperature.

of Cu(OTf)2, the desired product 6a was obtained in 72% yield (entry 7). Delightfully, when the reaction was performed with 10 mol % of CuOTf·toluene complex as a catalyst in DCE, 6a was isolated in 85% yield (entry 8). Further optimization studies were carried out with other metal catalysts such as Agand Au-based salts. Although all of these catalysts were found to be suitable for this transformation, the yield of 6a was moderate in those cases (entries 9−11). PdCl2 failed to catalyze this transformation (entry 12). To find out the best solvent for this transformation, the optimization studies have been extended by performing the reaction in other solvents, such as CH2Cl2, toluene, and acetonitrile using the CuOTf·toluene complex as a catalyst (entries 13−15). However, the isolated yields of 6a in those cases were inferior when compared to that of the reaction in DCE (entry 8). Due to its volatile nature, 3 equiv of Me3SiN3 with respect to 5a was used in all of the optimization experiments (entries 1−15) to drive the reaction to completion, as lowering the amount of Me3SiN3 to 2 equiv significantly reduced the yield of 6a (entry 16). No product formation was observed when NaN3 was used instead of Me3SiN3 (entry 17). After finding the optimal condition for this transformation (Table 1, entry 8), we shifted our attention to evaluate the substrate scope of this transformation and the results are summarized in Table 2. The 2-alkynylated p-QMs (5b−o), substituted with electron-rich, electron-poor, and halo-substituted aryl substituents at the alkyne part, reacted with Me3SiN3 under the standard conditions and provided the corresponding fused 1,2,3-triazole derivatives (6b−o) in moderate to good yields. Other p-QMs, having sterically

Scheme 2. General Scheme for the Synthesis of 2Alkynylated p-QMs

by treating 5a with Me3SiN3 under various reaction conditions, and the results are disclosed in Table 1. Our initial attempts using CuI (10 mol %) as a catalyst in DCE (1,2-dichloroethane) did not give any fruitful results, as the expected fused 1,2,3-triazole derivative 6a was not observed either at room temperature or at 60 °C (entries 1 and 2). However, when the reaction was performed by adding 2,2′-bipyridyl as a ligand, the expected product 6a was obtained in 15% yield (entry 3). Interestingly, when the reaction was carried with CuI in MeCN, 6a was obtained in 70% yield after 36 h (entry 4). Cu(II)-Based catalysts such as Cu(OAc)2 and CuSO4 were found to drive this transformation at 60 °C in DCE; however, 6a was observed in traces and 27% yield, respectively (entries 5 and 6). In the case 8597

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

Note

The Journal of Organic Chemistry Table 3. Substrate Scopea

Table 2. Substrate Scope with Different 2-Alkynylated pQMsa

a

Reactions were carried out with 0.04−0.08 mmol scale of 7c−e. Reactions were carried out with 0.26 and 0.27 mmol of 7a and 7b, respectively.

b

Scheme 3. Control Experiments for Mechanistic Studies a

Most of the reactions were carried out with 0.04−0.08 mmol scale of 5. bReactions were carried out with 0.26−0.38 mmol scale of 5, and the details can be found in the Experimental Section.

hindered substituents at the alkyne part (5p and 5q), also provided the respective fused 1,2,3-triazole derivatives 6p and 6q in 50 and 64% yields, respectively. In the case of 5r, where the alkyne is substituted with a thiazole ring, the expected product 6r was obtained in 80% isolated yield. This transformation also worked well in the cases of p-QMs 5s−v (where the alkyne part is substituted with aliphatic groups), and the products 6s−v were obtained in the range of 57−81% yields. In the case of p-QM (5w), derived from 2,6-dimethyl phenol, the expected product 6w was obtained in 40% yield. After exploring the substrate scope of alkynylated p-QMs having various aryl and alkyl substituents in the alkyne part (Table 2), we also evaluated the scope and limitation of this transformation by varying the substituent at aryl group of pQMs, and the results are presented in Table 3. In general, the pQMs 7a−d (substituted with electron-rich aryl groups) reacted efficiently and provided the respective 1,2,3-triazole-fused isoindoline derivatives (8a−d) in moderate yields (60−66%). Fluoro-substituted p-QM 7e also underwent smooth conversion to the expected product 8e in 60% isolated yield. We then shifted our attention to understand the mechanism of this transformation. One can assume that there are two possibilities through which this transformation could proceed. One possibility is that the o-alkynylated p-QM may initially undergo 1,6-conjugate addition with Me3SiN3 followed by the intramolecular click reaction through the azide intermediate 10 (path A, Scheme 3). Another possibility could be the initial formation of 1,2,3-triazole 11 followed by intramolecular 1,6-

conjugate addition (path B, Scheme 3). To confirm the involvement of any intermediate in this transformation, the optimal reaction (entry 8, Table 1) was carefully monitored by TLC analysis. Apart from the spots that correspond to p-QM (5a) and the product (6a), another new spot was observed in TLC between the spots of 5a and 6a. Interestingly, the intensity of this spot was gradually decreased over a period of time, and at the same time , the intensity of 6a increased gradually. This clearly indicates that the new spot indeed 8598

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

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The Journal of Organic Chemistry

silica gel 60 F254 TLC plates. Column chromatography was carried out through silica gel (100−200 mesh) using EtOAc/hexane as an eluent. General Procedure for the Synthesis of 2-Alkynylated pQuinone Methides (5a−w and 7a−e). Terminal acetylene (1.22 mmol) was added to a solution of PdCl2(PPh3)2 (0.04 mmol), CuI (0.04 mmol), and 2-bromo-p-quinone methide (0.8 mmol) in triethylamine (5 mL) at room temperature, and the reaction mixture was heated to 70 °C and stirred vigorously under an inert atmosphere. After the reaction was complete (by TLC), triethylamine was removed under reduced pressure and the residue was then diluted with dichloromethane (30 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (20 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography using hexane/ EtOAc to get pure alkynylated p-quinone methide derivatives. 2,6-Di-tert-butyl-4-(2-(phenylethynyl)benzylidene)cyclohexa-2,5dienone (5a): Rf = 0.6 (5% EtOAc in hexane); yellow solid (290 mg, 91% yield); mp = 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.1 Hz, 1H), 7.53−7.47 (m, 3H), 7.45−7.39 (m, 4H), 7.37− 7.36 (m, 3H), 7.09 (s, 1H), 1.36 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.1, 137.7, 135.1, 133.0, 132.8, 131.7, 131.7, 130.8, 129.0, 128.9, 128.6, 128.3, 124.3, 123, 95.7, 87.7, 35.6, 35.2, 29.7, 29.6; FT-IR (neat) 2957, 2217, 1614 cm−1; HRMS (ESI) m/z calcd for C29H31O [M + H]+ 395.2375, found 395.2358. 4-(2-([1,1′-Biphenyl]-4-ylethynyl)benzylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (5b): Rf = 0.5 (5% EtOAc in hexane); orange solid (258 mg, 69% yield); mp = 127−129 °C; 1H NMR (400 MHz, CDCl3) δ 7.69−7.67 (m, 1H), 7.63−7.61 (m, 4H), 7.60−7.57 (m, 3H), 7.50−7.44 (m, 5H), 7.43−7.37 (m, 2H), 7.14 (s, 1H), 1.40 (s, 9H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.6, 141.1, 140.3, 137.7, 135.0, 132.9, 132.8, 132.1, 130.7, 129, 128.97, 128.3, 127.9, 127.2, 127.1, 127.1, 124.3, 121.8, 95.7, 88.4, 35.6, 35.2, 29.7, 29.6; FT-IR (neat) 2957, 2214, 1614 cm−1; HRMS (ESI) m/z calcd for C35H35O [M + H]+ 471.2688, found 471.2708. 2,6-Di-tert-butyl-4-(2-(p-tolylethynyl)benzylidene)cyclohexa-2,5dienone (5c): Rf = 0.6 (5% EtOAc in hexane); orange solid (254 mg, 77% yield); mp = 148−150 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7 Hz, 1H), 7.54 (s, 1H), 7.47−7.44 (m, 2H), 7.41−7.36 (m, 4H), 7.17 (d, J = 7.7 Hz, 2H), 7.1 (s, 1H), 2.38 (s, 3H), 1.36 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.2, 139.1, 137.6, 135.1, 132.9, 132.7, 131.6, 130.7, 129.3, 129, 128.4, 128.1, 124.5, 119.9, 96, 87.1, 35.6, 35.2, 29.7, 29.6, 21.7; FT-IR (neat) 2957, 2217, 1614 cm−1; HRMS (ESI) m/z calcd for C30H33O [M + H]+ 409.2531, found 409.2513 2,6-Di-tert-butyl-4-(2-((4-(tert-butyl)phenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5d): Rf = 0.6 (5% EtOAc in hexane); orange solid (292 mg, 67% yield); mp = 85−87 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7 Hz, 1H), 7.53 (s, 1H), 7.46−7.44 (m, 4H), 7.40−7.38 (m, 4H), 7.09 (s, 1H), 1.36 (s, 9H), 1.33 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 152.3, 149.4, 148.1, 141.2, 137.6, 135.1, 132.9, 132.7, 131.5, 130.8, 129, 128.3, 128.2, 125.6, 124.6, 120, 96, 87.1, 35.6, 35.2, 35, 31.3, 29.7, 29.65; IR (neat) 2958, 2217, 1615 cm−1; HRMS (ESI) m/z calcd for C33H39O [M + H]+ 451.3001, found 451.3018. 2,6-Di-tert-butyl-4-(2-((2,4,5-trimethylphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5e): Rf = 0.6 (5% EtOAc in hexane); orange solid (248 mg, 70% yield); mp = 125−127 °C; 1H NMR (400 MHz, CDCl3) δ 7.65−7.61 (m, 1H), 7.58 (s, 1H), 7.49− 7.45 (m, 2H), 7.42−7.36 (m, 2H), 7.27 (s, 1H), 7.08 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 2.44 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.35 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.5, 137.9, 137.6, 137.4, 135.2, 134.1, 133.1, 132.7, 132.4, 131.2, 130.5, 129.0, 128.2, 128.0, 125.0, 119.9, 95.4, 90.7, 35.6, 35.2, 29.7, 29.6, 20.4, 19.9, 19.3; IR (neat) 2956, 2207, 1614 cm−1; HRMS (ESI) m/z calcd for C32H37O [M + H]+ 437.2844, found 437.2828. 2,6-Di-tert-butyl-4-(2-((4-methoxyphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5f): Rf = 0.5 (5% EtOAc in hexane); orange solid (240 mg, 70% yield); mp = 139−141 °C; 1H NMR (400 MHz, CDCl3) δ 7.64−7.59 (m, 1H), 7.53 (s, 1H), 7.46−7.42 (m, 4H),

corresponds to the intermediate. However, the formation of the intermediate was found to be reversible during chromatographic purification. So, we decided to monitor this transformation by NMR spectroscopy. In this context, an experiment was carried out in CDCl3 (instead of DCE) in a NMR tube using 10 mol % of AgSbF6 (entry 9, Table 1)19 at 45 °C for 45 min and the crude mixture was analyzed by 1H NMR (400 MHz). The 1H NMR analysis of the crude mixture (after the complete consumption of 5a) revealed that there were two signals at 6.28 and 5.19 ppm, which correspond to the benzylic proton and the phenolic −OH proton,20 respectively. (Please see the Supporting Information for the spectrum.) This clearly confirms that the intermediate is indeed the azido derivative 10. The other possible 1,2,3-triazole intermediate 11 was not observed at all. The presence of alkyne moiety in 10 was also confirmed by 13C NMR spectroscopic analysis (signals at 94.9 and 87.4 ppm for alkyne) and IR spectroscopic analysis (strong band at 2090 cm−1 for the azido group). To confirm the involvement of the azide intermediate, another control experiment was performed with p-QM 1218b (in which the alkyne group is substituted at the para-position of the aryl group) using CuOTf·toluene as a catalyst under standard conditions (entry 8, Table 1) for 24 h, and the crude reaction mixture was analyzed by NMR spectroscopy after removing the solvent (Scheme 3). The 1H NMR [signals at 5.65 (s) and 5.26 (s) for benzylic and phenolic −OH, respectively] and 13C NMR [signals at 89.9 and 89.2 ppm for alkynes] spectra confirm that the product obtained was 13. The IR spectra of 13 also confirmed the presence of azide (2098 cm−1) and alkyne (2130 cm−1) functionalities. Interestingly, 13 was observed as the sole product, and the other possible 1,2,3-triazole product was not at all observed. On the basis of these observations, one can unambiguously confirm that the reaction is actually proceeding through path A (Scheme 3), i.e., via the azide intermediate 10. In conclusion, we have developed a Cu-catalyzed one-pot method for the synthesis of fused 1,2,3-triazole derivatives through 1,6-conjugate addition of Me3SiN3 followed by intramolecular click cycloaddition. A variety 1,2,3-triazolefused isoindoline derivatives could be accessed in moderate to good yields through this protocol. Sensitive functional groups such as ester and nitrile were well tolerated under the reaction conditions. Since many fused 1,2,3-triazole derivatives are proven to possess significant biological activities, we believe these new set of 1,2,3-triazole-fused isoindoline derivatives would reflect a similar kind of biological activities and find some suitable therapeutic applications in near future.

■

EXPERIMENTAL SECTION

General Information. All reactions were carried out under an argon atmosphere employing flame-dried glassware. Most of the reagents and starting materials were purchased from commercial sources and used as such. All of the 2-bromo-p-quinone methides and 4-(2-bromobenzyl)-2,6-dimethylphenol were prepared by following a literature procedure.18a,21 Melting points were recorded on an SMP20 melting point apparatus and were uncorrected. 1H, 13C, and 19F spectra were recorded in CDCl3 (400, 100, and 376 MHz, respectively) on a Bruker FT-NMR spectrometer. Chemical shift (δ) values are reported in parts per million (ppm) relative to TMS, and the coupling constants (J) are reported in hertz (Hz). High resolution mass spectra were recorded on a Waters Q-TOF Premier-HAB213 spectrometer. FT-IR spectra were recorded on a Perkin−Elmer FT-IR spectrometer. Thin layer chromatography was performed on Merck 8599

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

Note

The Journal of Organic Chemistry 7.41−7.35 (m, 2H), 7.09 (d, J = 2.2 Hz, 1H), 6.90−6.87 (m, 2H), 3.84 (s, 3H), 1.36 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 160.1, 149.4, 148.1, 141.3, 137.5, 135.1, 133.2, 132.8, 132.7, 130.7, 129, 128.4, 128, 124.7, 115.1, 114.2, 95.9, 86.5, 55.5, 35.6, 35.2, 29.7, 29.6; IR (neat) 2957, 2212, 1614 cm−1; HRMS (ESI) m/z calcd for C30H33O2 [M + H]+ 425.2481, found 425.2474. 2,6-Di-tert-butyl-4-(2-((4-methoxy-2-methylphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5g): Rf = 0.4 (5% EtOAc in hexane); orange solid (288 mg, 81% yield); mp = 166−168 °C; 1H NMR (400 MHz, CDCl3) δ 7.64−7.61 (m, 1H), 7.58 (s, 1H), 7.48− 7.44 (m, 3H), 7.42−7.38 (m, 2H), 7.08−7.07 (m, 1H), 6.79−6.78 (m, 1H), 6.75−6.72 (m, 1H), 3.82 (s, 3H), 2.49 (s, 3H), 1.35 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 160.1, 149.4, 148.1, 142.1, 141.5, 137.2, 135.1, 133.5, 132.6, 132.4, 130.5, 129, 128.2, 127.9, 125, 115.3, 115.1, 111.6, 95.2, 90.3, 55.4, 35.6, 35.2, 29.7, 29.7, 21.3; IR (neat) 2956, 2204, 1613 cm−1; HRMS (ESI) m/z calcd for C31H35O2 [M + H]+ 439.2637, found 439.2619. 2,6-Di-tert-butyl-4-(2-((4-phenoxyphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5h): Rf = 0.5 (5% EtOAc in hexane); orange gummy solid (259 mg, 67% yield); 1H NMR (400 MHz, CDCl3) δ 7.64−7.62 (m, 1H), 7.52 (s, 1H), 7.48−7.43 (m, 4H), 7.41−7.35 (m, 4H), 7.16 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H) 7.05 (d, J = 7.7 Hz, 2H), 7−6.96 (m, 2H), 1.35 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 158.2, 156.4, 149.4, 148.1, 141.1, 137.6, 135, 133.4, 132.9, 132.8, 130.8, 130.1, 129, 128.4, 128.2, 124.4, 124.2, 119.7, 118.5, 117.4, 95.4, 87.1, 35.6, 35.2, 29.7, 29.6; IR (neat) 2957, 2214, 1614 cm−1; HRMS (ESI) m/z calcd for C35H35O2 [M + H]+ 487.2637, found 487.2650. 2,6-Di-tert-butyl-4-(2-((2-chlorophenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5i): Rf = 0.6 (5% EtOAc in hexane); orange solid (232 mg, 66% yield); mp = 130−132 °C; 1H NMR (400 MHz, CDCl3) δ 7.71−7.67 (m, 2H), 7.57−7.55 (m, 1H), 7.52−7.50 (m, 1H), 7.46−7.38 (m, 4H), 7.31−7.24 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 1.35 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.6, 148.1, 141.2, 138, 136.1, 135.3, 133.4, 132.9, 132.6, 130.5, 129.8, 129.6, 128.9, 128.7, 128.1, 126.8, 124, 123, 92.7, 92.6, 35.6, 35.2, 29.7; IR (neat) 2956, 2207, 1614 cm−1; HRMS (ESI) m/z calcd for C29H30ClO [M + H]+ 429.1985, found 429.1967. 2,6-Di-tert-butyl-4-(2-((3-fluorophenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5j): Rf = 0.6 (5% EtOAc in hexane); yellow solid (211 mg, 63% yield); mp = 128−130 °C; 1H NMR (400 MHz, CDCl3) δ 7.65−7.63 (m, 1H), 7.49−7.46 (m, 2H), 7.44−7.38 (m, 3H), 7.35−7.28 (m, 2H), 7.21−7.18 (m, 1H), 7.09−7.04 (m, 2H), 1.36 (s, 9H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 162.5 (d, JC−F = 245.4 Hz), 149.5, 148.3, 140.6, 137.9, 134.9, 133.04, 133.0, 130.8, 130.2 (d, JC−F = 8.6 Hz), 129.0, 128.7, 128.2, 127.6 (d, JC−F = 3.0 Hz), 124.8 (d, JC−F = 9.5 Hz), 123.7, 118.5 (d, JC−F = 22.7 Hz), 116.2 (d, JC−F = 21.1 Hz), 94.2 (d, JC−F = 3.4 Hz), 88.6, 35.6, 35.2, 29.7, 29.6; 19F NMR (376 MHz, CDCl3) δ −112.58; IR (neat) 2957, 2210, 1614 cm−1; HRMS (ESI) m/z calcd for C29H30FO [M + H]+ 413.2281, found 413.2263. 2,6-Di-tert-butyl-4-(2-((2-(trifluoromethyl)phenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5k): Rf = 0.6 (5% EtOAc in hexane); yellow solid (235 mg, 63% yield); mp = 122−124 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.8 Hz, 1H), 7.68−7.65 (m, 2H), 7.61 (s, 1H), 7.55−7.50 (m, 2H), 7.47−7.38 (m, 4H), 7.15 (d, J = 1.8 Hz, 1H), 1.36 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.9, 149.6, 148.1, 140.7, 138.1, 135.4, 134.2, 134.2, 133.2, 132.8, 131.7, 130.6, 129.0, 128.9, 128.5, 128.0, 126.1 (q, JC−F = 4.5 Hz), 123.8 (q, JC−F = 271.7 Hz), 123.7, 121.2 (q, JC−F = 2.1 Hz), 93.1, 91.4, 35.6, 35.2, 29.6, 29.59; 19F NMR (376 MHz, CDCl3) δ −61.91; IR (neat) 2957, 2214, 1614 cm−1; HRMS (ESI) m/z calcd for C30H30F3O [M + H]+ 463.2249, found 463.2232. 4-((2-((3,5-Di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)phenyl)ethynyl)benzonitrile (5l): Rf = 0.6 (5% EtOAc in hexane); yellow solid (220 mg, 65% yield); mp = 194−196 °C; 1H NMR (400 MHz, CDCl3) δ 7.66−7.63 (m, 3H), 7.57−7.54 (m, 2H), 7.48−7.47 (m, 2H), 7.44−7.38 (m, 3H), 7.07 (d, J = 2.3 Hz, 1H), 1.35 (s, 9H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 149.6, 148.4, 140.2, 138.0, 134.7, 133.2, 133.19, 132.3, 132.2, 130.8, 129.2,

129.0, 128.2, 127.9, 123.0, 118.5, 112.0, 93.5, 92.0, 35.6, 35.3, 29.7, 29.6; IR (neat) 2956, 2231, 2205, 1614 cm−1; HRMS (ESI) m/z calcd for C30H30NO [M + H]+ 420.2327, found 420.2309. 4-((2-((3,5-Di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)phenyl)ethynyl)-2-fluorobenzonitrile (5m): Rf = 0.2 (5% EtOAc in hexane); orange solid (210 mg, 60% yield); mp = 197−199 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.5 Hz, 1H), 7.61− 7.58 (m, 1H), 7.51−7.46 (m, 2H), 7.44−7.40 (m, 2H), 7.37−7.28 (m, 3H), 7.07 (d, J = 2.2 Hz, 1H), 1.35 (s, 9H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.6, 162.8 (d, JC−F = 258.3 Hz), 149.6, 148.5, 139.8, 138.2, 134.6, 133.5, 133.4, 133.3, 130.9, 130.1 (d, JC−F = 9.7 Hz), 129.6, 129.0, 128.1, 128.0 (d, JC−F = 3.5 Hz), 122.4, 119.2 (d, JC−F = 21.0 Hz), 113.7, 101.4 (d, JC−F = 15.6 Hz), 93.2, 92.3 (d, JC−F = 3.1 Hz), 35.5, 35.2, 29.6, 29.57; 19F NMR (376 MHz, CDCl3) δ −106.02; IR (neat) 2960, 2231, 2204, 1613 cm−1; HRMS (ESI) m/z calcd for C30H29FNO [M + H]+ 438.2233, found 438.2216. Methyl 4-((2-((3,5-Di-tert-butyl-4-oxocyclohexa-2,5-dien-1ylidene)methyl)phenyl)ethynyl)benzoate (5n): Rf = 0.3 (5% EtOAc in hexane); yellow solid (200 mg, 55% yield); mp = 159−161 °C; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.49−7.45 (m, 3H), 7.40−7.38 (m, 2H), 7.09 (s, 1H), 3.93 (s, 3H), 1.36 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 166.6, 149.5, 148.3, 140.6, 137.9, 134.9, 133.1, 133, 131.6, 130.8, 130, 129.7, 129, 128.8, 128.2, 127.6, 123.6, 94.7, 90.6, 52.5, 35.6, 35.2, 29.7, 29.6; IR (neat) 2956, 2213, 1726, 1614 cm−1; HRMS (ESI) m/z calcd for C31H33O3 [M + H]+ 453.2430, found 453.2413. 2,6-Di-tert-butyl-4-(2-((6-methoxynaphthalen-2-yl)ethynyl)benzylidene)cyclohexa-2,5-dienone (5o): Rf = 0.1 (5% EtOAc in hexane); orange solid (240 mg, 62% yield); mp = 148−150 °C; 1H NMR (400 MHz, CDCl3) δ 7.95, (s, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.68−7.66 (m, 1H), 7.58 (s, 1H), 7.51−7.46 (m, 3H), 7.44−7.38 (m, 2H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 7.14−7.12 (m, 2H), 3.94 (s, 3H), 1.37 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 158.6, 149.4, 148.1, 141.3, 137.7, 135.1, 134.5, 132.9, 132.8, 131.5, 130.8, 129.5, 129.0, 128.9, 128.5, 128.4, 128.2, 127.1, 124.5, 119.8, 117.8, 106.0, 96.4, 87.5, 55.5, 35.6, 35.2, 29.7, 29.6; FT-IR (neat) 2956, 2208, 1614 cm−1; HRMS (ESI) m/z calcd for C34H35O2 [M + H]+ 475.2637, found 475.2618. 2,6-Di-tert-butyl-4-(2-(pyren-1-ylethynyl)benzylidene)cyclohexa2,5-dienone (5p): Rf = 0.3 (5% EtOAc in hexane); orange solid (320 mg, 71% yield); mp = 178−180 °C; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 9.1 Hz, 1H), 8.27−8.20 (m, 3H), 8.18−8.13 (m, 3H), 8.11−8.03 (m, 2H), 7.84−7.79 (m, 2H), 7.56−7.45 (m, 4H), 7.24 (d, J = 2.2 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.6, 148.3, 141.4, 137.8, 135.1, 132.9, 132.8, 132.1, 131.7, 131.3, 131.0, 130.7, 129.6, 129.1, 128.7 (2C), 128.6, 128.4, 128.3, 127.3, 126.5, 125.9, 125.89, 125.4, 124.7, 124.6, 124.4, 117.3, 95.3, 93.5, 35.6, 35.3, 29.8, 29.7; IR (neat) 2955, 2197, 1613 cm−1; HRMS (ESI) m/z calcd for C39H34NaO [M + Na]+ 541.2507, found 541.2515. 2,6-Di-tert-butyl-4-(2-(phenanthren-9-ylethynyl)benzylidene)cyclohexa-2,5-dienone (5q): Rf = 0.3 (5% EtOAc in hexane); orange gummy solid (192 mg, 48% yield); 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.1 Hz, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J = 7.3 Hz, 1H), 7.81−7.77 (m, 1H), 7.73− 7.60 (m, 5H), 7.54−7.43 (m, 4H), 7.19 (d, J = 2.2 Hz, 1H), 1.39 (s, 9H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.6, 148.3, 141.2, 137.8, 135.1, 133.0, 132.9, 132.4, 131.2, 131.1, 130.8, 130.6, 130.3, 129.1, 128.8, 128.5, 128.3, 127.9, 127.3, 127.27, 127.2, 126.9, 124.4, 123.1, 122.8, 119.4, 94.2, 92.2, 35.6, 35.3, 29.7, 29.6; IR (neat) 2955, 2197, 1613 cm−1; HRMS (ESI) m/z calcd for C37H35O [M + H]+ 495.2688, found 495.2664. 2,6-Di-tert-butyl-4-(2-(thiophen-3-ylethynyl)benzylidene)cyclohexa-2,5-dienone (5r): Rf = 0.4 (5% EtOAc in hexane); yellow solid (175 mg, 54% yield); mp = 127−129 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.5, 1H), 7.53−7.51 (m, 2H), 7.47−7.36 (m, 4H), 7.33−7.31 (m, 1H), 7.18 (d, J = 4.9, Hz, 1H), 7.09 (s, 1H), 1.36 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.1, 137.6, 135.1, 132.9, 132.8, 130.8, 129.9, 129.2, 129.0, 8600

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

Note

The Journal of Organic Chemistry

17.0, 16.4; FT-IR (neat) 2922, 2214 1617 cm−1; HRMS (ESI) m/z calcd for C23H19O [M + H]+ 311.1436, found 311.1449. 2,6-Di-tert-butyl-4-(4-methyl-2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7a): Rf = 0.6 (5% EtOAc in hexane); orange gummy solid (290 mg, 88% yield); 1H NMR (400 MHz, CDCl3) δ 7.53−7.50 (m, 3H), 7.49−7.46 (m, 2H), 7.39−7.35 (m, 4H), 7.23 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 2.41 (s, 3H), 1.36 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.2, 147.9, 141.3, 139.4, 135.2, 134.9, 133.5, 132.3, 131.7, 130.7, 129.4, 128.8, 128.6, 128.4, 124.2, 123.0, 95.3, 87.8, 35.5, 35.2, 29.7, 29.6, 21.3; FTIR (neat) 2956, 2211, 1613 cm−1; HRMS (ESI) m/z calcd for C30H33O [M + H]+ 409.2531, found 409.2521. 2,6-Di-tert-butyl-4-(5-methoxy-2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7b): Rf = 0.5 (5% EtOAc in hexane); brown solid (282 mg, 82% yield); mp = 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.5 Hz, 1H), 7.50−7.47 (m, 4 H), 7.37−7.33 (m, 3H), 7.09 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 6.0, 2.5 Hz, 1H), 3.87 (s, 3H), 1.35 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 159.4, 149.4, 148.2, 141.0, 139.0, 135.1, 134.2, 132.9, 131.6, 128.54, 128.51, 128.3, 123.3, 116.6, 115.7, 115.5, 94.2, 87.7, 55.6, 35.6, 35.2, 29.69, 29.67; IR (neat) 2956, 2922, 2218, 1614, 1457, 1361, 1260, 835, 751 cm−1; HRMS (ESI) m/z calcd for C30H33O2 [M + H]+ 425.2481, found 425.2465. 2,6-Di-tert-butyl-4-(2,4-dimethoxy-6-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7c): Rf = 0.1 (5% EtOAc in hexane); yellow solid (232 mg, 63% yield); mp = 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.26−7.24 (m, 2H), 7.22−7.21 (m, 4H), 7.19 (s, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 2.2 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 1.38 (s, 9H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.9, 161.2, 159.0, 147.14, 147.10, 137.8, 134.9, 133.2, 131.6, 130.6, 128.8, 128.4, 125.0, 122.7, 120.5, 108.0, 99.6, 93.8, 89.1, 55.8, 55.7, 35.2, 35.1, 29.7, 29.4; IR (neat) 2956, 2346, 1614 cm−1; HRMS (ESI) m/z calcd for C31H35O3 [M + H]+ 455.2586, found 455.2571. 2,6-Di-tert-butyl-4-(3,5-dimethoxy-2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7d): Rf = 0.1 (5% EtOAc in hexane); brown solid (255 mg, 81% yield); mp = 172−174 °C; 1H NMR (400 MHz, CDCl3) δ 7.52−7.49 (m, 4H), 7.36−7.29 (m, 3H), 7.09 (d, J = 2.0 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 1.35 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 161.8, 160.4, 149.3, 148.2, 141.3, 140.0, 135.1, 133.0, 131.6, 128.4 (2C), 128.3, 123.7, 106.9, 106.4, 99.5, 98.8, 84.1, 56.3, 55.7, 35.6, 35.2, 29.7, 29.6; IR (neat) 2956, 2346, 1614 cm−1; HRMS (ESI) m/z calcd for C31H35O3 [M + H]+ 455.2586, found 455.2571. 2,6-Di-tert-butyl-4-(5-fluoro-2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7e): Rf = 0.6 (5% EtOAc in hexane); yellow solid (240 mg, 73% yield); mp = 132−134 °C; 1H NMR (400 MHz, CDCl3) δ 7.67−7.62 (m, 1H), 7.52−7.49 (m, 2H), 7.44 (s, 1H), 7.42−7.37 (m, 4H), 7.20 (dd, J = 9.7, 2.7 Hz, 1H), 7.15−7.09 (m, 2H), 1.38 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 162.1 (d, JC−F = 249.1 Hz), 149.9, 148.6, 139.7 (d, JC−F = 8.3 Hz), 139.1 (d, JC−F = 2.0 Hz), 134.8, 134.7, 133.5, 131.7, 128.9, 128.6, 127.7, 122.8, 120.4 (d, JC−F = 3.2 Hz), 117.5 (d, JC−F = 23.0 Hz), 116.3 (d, JC−F = 22.1 Hz), 95.3 (d, JC−F = 1.5 Hz), 86.8, 35.6, 35.3, 29.7, 29.6; 19F NMR (376 MHz, CDCl3) δ −110.37; IR (neat) 2957, 1614 cm−1; HRMS (ESI) m/z calcd for C29H30FO [M + H]+ 413.2281, found 413.2272. General Procedure for the Synthesis of 1,2,3-Triazole-fused Isoindoline Derivatives (6a−w and 8a−e). A mixture of 2alkynylated p-quinone methide (0.5 mmol), TMSN3 (1.5 mmol), and CuOTf·toluene (0.05 mmol) in DCE (5 mL) was stirred in a closed vial under an inert atmosphere at 60 °C, and the progress was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure and the residue was directly loaded on a silica gel column, eluting with a mixture of EtOAc/hexane to obtain the pure 1,2,3-triazole-fused isoindoline derivatives. 2,6-Di-tert-butyl-4-(3-phenyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8yl)phenol (6a): performed in 0.063 mmol scale of 5a; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (23.3 mg, 85% yield); mp = 201−

128.29, 128.27, 125.8, 124.2, 122.0, 90.8, 87.2, 35.6, 35.2, 29.7, 29.6; FT-IR (neat) 2956, 2208, 1614 cm−1; HRMS (ESI) m/z calcd for C27H29OS [M + H]+ 401.1939, found 401.1952. 3-(2-((3,5-Di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)phenyl)prop-2-yn-1-yl Acetate (5s): Rf = 0.3 (5% EtOAc in hexane); yellow gummy solid (154 mg, 50% yield); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.5 Hz, 1H), 7.44−7.40 (m, 3H), 7.38− 7.33 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 4.94 (s, 2H), 2.13 (s, 3H), 1.34 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 170.3, 149.6, 148.1, 140.6, 138.0, 135.1, 133.2, 132.8, 130.7, 128.9, 128.8, 128.0, 123.1, 89.4, 84.5, 52.9, 35.6, 35.2, 29.6, 20.9; IR (neat) 2956, 2231, 1747, 1614 cm−1; HRMS (ESI) m/z calcd for C26H30NaO3 [M + Na]+ 413.2093, found 413.2076. 2,6-Di-tert-butyl-4-(2-(3-cyclohexylprop-1-yn-1-yl)benzylidene)cyclohexa-2,5-dienone (5t): Rf = 0.7 (5% EtOAc in hexane); orange solid (217 mg, 66% yield); mp = 87−89 °C; 1H NMR (400 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.42−7.40 (m, 2H), 7.36−7.30 (m, 2H), 7.05 (d, J = 2.0 Hz, 1H), 2.37 (d, J = 6.5 Hz, 2H), 1.87 (d, J = 11.7 Hz, 2H), 1.77−1.73 (m, 2H), 1.70−1.53 (m, 3H), 1.34 (s, 9H), 1.28 (s, 9H), 1.21−1.14 (m, 2H), 1.12−1.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.3, 147.9, 141.9, 137.5, 135.2, 132.8, 132.2, 130.6, 128.9, 128.3, 127.5, 125.3, 96.4, 79.9, 37.6, 35.6, 35.1, 32.9, 29.7, 29.6, 27.6, 26.4, 26.3; IR (neat) 2924, 2225, 1615 cm−1; HRMS (ESI) m/z calcd for C30H39O [M + H]+ 415.3001, found 415.3018. 2,6-Di-tert-butyl-4-(2-(cyclohexylethynyl)benzylidene)cyclohexa2,5-dienone (5u): Rf = 0.7 (5% EtOAc in hexane); orange gummy solid (158 mg, 50% yield); 1H NMR (400 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.42−7.41 (m, 2H), 7.36−7.29 (m, 2H), 7.04 (d, J = 1.8 Hz, 1H), 2.72−2.69 (m, 1H), 1.85−1.75 (m, 6H), 1.55−1.39 (m, 4H), 1.34 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.3, 147.9, 141.9, 137.6, 135.2, 132.7, 132.2, 130.4, 128.9, 128.3, 127.5, 125.3, 101.5, 79.1, 35.6, 35.1, 32.6, 29.7, 29.6, 26.1, 24.7; IR (neat) 2956, 2228, 1614 cm−1; HRMS (ESI) m/z calcd for C29H37O [M + H]+ 401.2844, found 401.2830. 2,6-Di-tert-butyl-4-(2-(cyclopropylethynyl)benzylidene)cyclohexa-2,5-dienone (5v): Rf = 0.7 (5% EtOAc in hexane); orange gummy solid (146 mg, 51% yield); 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.0 Hz, 1H), 7.43 (s, 1H), 7.40−7.38 (m, 2H), 7.34−7.28 (m, 2H), 7.06 (d, J = 1.7 Hz, 1H), 1.53−1.47 (m, 1H), 1.35 (s, 9H), 1.28 (s, 9H), 0.94−0.88 (m, 2H), 0.83−0.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.3, 147.9, 141.7, 137.6, 135.1, 132.9, 132.3, 130.6, 128.9, 128.3, 127.5, 125.1, 100.5, 74.1, 35.5, 35.2, 29.7, 9.2, 0.6; IR (neat) 2957, 2228, 1614 cm−1; HRMS (ESI) m/z calcd for C26H31O [M + H]+ 359.2375, found 359.2390. 4-(2-Bromobenzylidene)-2,6-dimethylcyclohexa-2,5-dienone (14). A mixture of potassium ferricyanide (1.04 g, 3.17 mmol) and potassium hydroxide (0.19 g, 3.3 mmol, 4.2 equiv) in water (5 mL) was added to a solution of 4-(2-bromobenzyl)-2,6-dimethylphenol (0.23 g, 0.79 mmol) in hexanes (25 mL) under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. The aqueous layer was separated and extracted with hexanes (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude mixture was filtered through a short plug of silica gel column to afford pure 4(2-bromobenzylidene)-2,6-dimethylcyclohexa-2,5-dienone (0.21 g, 92% yield) as a yellow solid: Rf = 0.4 (10% EtOAc in hexane); mp = 108−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.43−7.39 (m, 2H), 7.30−7.25 (m, 2H), 7.22 (s, 1H), 7.13 (s, 1H), 2.07 (s, 3H), 7.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.5, 141.1, 138.4, 138.1, 136.4, 135.7, 133.3, 132.5, 132.47, 131.3, 130.5, 127.5, 125.1, 17.0, 16.4; FT-IR (neat) 2922, 1619 cm−1; HRMS (ESI) m/z calcd for C15H14BrO [M + H]+ 289.0228, found 289.0220. 2,6-Dimethyl-4-(2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (5w): performed in 0.55 mmol scale of 18; Rf = 0.4 (10% EtOAc in hexane); orange gummy solid (40 mg, 24% yield); 1H NMR (400 MHz, CDCl3) δ 7.65−7.63 (m, 2H), 7.54−7.48 (m, 4H), 7.45− 7.36 (m, 6H), 7.14 (s, 1H), 2.09 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.6, 141.3, 138.8, 137.9, 137.4, 136.2, 132.9, 132.5, 131.7 (2C), 131.0, 129.2, 128.9, 128.6, 128.4, 124.4, 122.9, 96.0, 87.4, 8601

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

Note

The Journal of Organic Chemistry

2958 cm−1; HRMS (ESI) m/z calcd for C31H36N3O2 [M + H]+ 482.2808, found 482.2825. 2,6-Di-tert-butyl-4-(3-(4-phenoxyphenyl)-8H-[1,2,3]triazolo[5,1a]isoindol-8-yl)phenol (6h): performed in 0.051 mmol scale of 5h; Rf = 0.5 (25% EtOAc in hexane); pale yellow solid (14.3 mg, 53% yield); mp = 180−182 °C; 1H NMR (400 MHz, CDCl3) δ 8.00−7.96 (m, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.51−7.45 (m, 1H), 7.42−7.36 (m, 4H), 7.20−7.17 (m, 3H), 7.14−7.09 (m, 2H), 7.01 (s, 2H), 6.37 (s, 1H), 5.30 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 157.5, 157.1, 154.7, 146.8, 140.0, 137.5, 136.7, 130.0, 129.0, 128.7, 128.7, 127.4, 126.6, 126.4, 125.2, 124.7, 123.7, 121.1, 119.3, 119.2, 66.9, 34.5, 30.3; FT-IR (neat) 3628, 2958 cm−1; HRMS (ESI) m/z calcd for C35H36N3O2 [M + H]+: 530.2808, found 530.2830. 2,6-Di-tert-butyl-4-(3-(2-chlorophenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6i): performed in 0.058 mmol scale of 5j; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (17.4 mg, 64% yield); mp = 202−204 °C; 1H NMR (400 MHz, CDCl3) δ 7.82−7.78 (m, 1H), 7.60−7.55 (m, 2H), 7.45−7.40 (m, 3H), 7.39−7.36 (m, 2H), 7.00 (s, 2H), 6.41 (s, 1H), 5.30 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.0, 139.7, 136.7, 136.2, 133.3, 132.0, 130.7, 130.0, 129.97, 128.7, 128.6, 127.3, 127.2, 126.5, 124.6, 124.5, 123.3, 67.1, 34.5, 30.2; FT-IR (neat) 3629, 2959 cm−1; HRMS (ESI) m/z calcd for C29H31ClN3O [M + H]+ 472.2156, found 472.2139. 2,6-Di-tert-butyl-4-(3-(3-fluorophenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6j): performed in 0.27 mmol scale of 5k; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (100.3 mg, 82% yield); mp = 209−211 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.73 (dt, J = 9.8, 2.2 Hz, 1H), 7.54− 7.48 (m, 2H), 7.44−7.39 (m, 2H), 7.12 (td, J = 8.3, 2.1 Hz, 1H), 7.01 (s, 2H), 6.38 (s, 1H), 5.32 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 163.3 (d, JC−F = 244.4 Hz), 154.7, 146.9, 138.4 (d, JC−F = 2.5 Hz), 138.1, 136.7, 133.8 (d, JC−F = 8.5 Hz), 130.6 (d, JC−F = 8.4 Hz), 129.1, 129.0, 127.1, 126.1, 125.2, 124.7, 122.8 (d, JC−F = 7.9 Hz), 121.3, 115.1 (d, JC−F = 21.1 Hz), 114.1 (d, JC−F = 22.7 Hz), 67.0, 34.5, 30.2; 19F NMR (376 MHz, CDCl3) δ −112.38; FT-IR (neat) 3631, 2959 cm−1; HRMS (ESI) m/z calcd for C29H31FN3O [M + H]+ 456.2451, found 456.2434. 2,6-Di-tert-butyl-4-(3-(2-(trifluoromethyl)phenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6k): performed in 0.28 mmol scale of 5l; Rf = 0.4 (25% EtOAc in hexane); pale yellow solid (107 mg, 75% yield); mp = 172−174 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 1H), 7.71−7.65 (m, 2H), 7.63−7.59 (m, 1H), 7.37−7.32 (m, 4H), 6.98 (s, 2H), 6.40 (s, 1H), 5.30 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.1, 139.8, 136.7, 135.6, 132.7, 131.9, 130.1 (q, JC−F = 0.9 Hz), 129.1, 128.8, 128.7, 126.8, 126.7 (q, JC−F = 6.2 Hz), 126.5, 124.8, 124.3, 124.0 (d, JC−F = 272.3 Hz), 121.4, 67.1, 34.5, 30.2; 19F NMR (376 MHz, CDCl3) δ −58.67; FT-IR (neat) 3632, 2959 cm−1; HRMS (ESI) m/z calcd for C30H31F3N3O [M + H]+ 506.2419, found 506.2403. 4-(8-(3,5-Di-tert-butyl-4-hydroxyphenyl)-8H-[1,2,3]triazolo[5,1a]isoindol-3-yl) benzonitrile (6l): performed in 0.071 mmol scale of 5m; Rf = 0.4 (25% EtOAc in hexane); white solid (26.5 mg, 80% yield); mp = 261−263 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.56, 7.52 (m, 1H), 7.48−7.41 (m, 2H), 7.01 (s, 2H), 6.40 (s, 1H), 5.33 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.8, 147.1, 138.8, 137.6, 136.8, 136.2, 132.9, 129.4, 129.2, 127.5, 126.8, 125.8, 125.4, 124.7, 121.4, 119.0, 111.5, 67.1, 34.5, 30.2; FT-IR (neat) 3626, 2957, 2226 cm−1; HRMS (ESI) m/z calcd for C30H31N4O [M + H]+ 463.2498, found 463.2481. 4-(8-(3,5-Di-tert-butyl-4-hydroxyphenyl)-8H-[1,2,3]triazolo[5,1a]isoindol-3-yl)-2-fluorobenzonitrile (6m): performed in 0.057 mmol scale of 5n; Rf = 0.4 (25% EtOAc in hexane); white solid (21 mg, 77% yield); mp = 234−236 °C; 1H NMR (400 MHz, CDCl3) δ 7.93−7.89 (m, 3H), 7.79 (t, J = 6.8 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.00 (s, 2H), 6.40 (s, 1H), 5.34 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 163.7 (d, JC−F = 257.2 Hz), 154.9, 147.1, 139.2, 138.9 (d, JC−F = 8.9 Hz), 136.9, 136.7 (d, JC−F = 2.4 Hz), 134.1, 129.6, 129.3, 126.4, 125.6 (d, JC−F = 1.4 Hz), 124.7, 124.7, 123.1 (d, JC−F = 0.9 Hz), 121.5, 114.6 (d, JC−F = 21.1

203 °C; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.51−7.47 (m, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.40−7.37 (m, 2H), 7.01 (s, 2H), 6.37 (s, 1H), 5.30 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.7, 146.9, 139.5, 137.9, 136.7, 131.6, 129.1, 129.0, 128.7, 128.3, 127.4, 127.2, 126.4, 125.1, 124.7, 121.3, 66.9, 34.5, 30.2; FT-IR (neat) 3629, 2958 cm−1; HRMS (ESI) m/z calcd for C29H32N3O [M + H]+ 438.2545, found 438.2562. 4-(3-([1,1′-Biphenyl]-4-yl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)2,6-di-tert-butylphenol (6b): performed in 0.053 mmol scale of 5b; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (17.6 mg, 65% yield); mp = 219−221 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.71−7.69 (m, 2H), 7.53−7.43 (m, 3H), 7.44−7.37 (m, 3H), 7.03 (s, 2H), 6.39 (s, 1H), 5.31 (s, 1H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.7, 146.9, 141.0, 140.8, 139.2, 137.9, 136.7, 130.6, 129.0, 129.0, 128.7, 127.8, 127.6, 127.57, 127.4, 127.2, 126.3, 125.2, 124.7, 121.3, 66.9, 34.5, 30.2; FT-IR (neat) 3629, 2958 cm−1; HRMS (ESI) m/z calcd for C35H36N3O [M + H]+ 514.2858, found 514.2834. 2,6-Di-tert-butyl-4-(3-(p-tolyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8yl)phenol (6c): performed in 0.28 mmol scale of 5c; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (90 mg, 63% yield); mp = 198− 200 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.52−7.48 (m, 1H), 7.43−7.38 (m, 4H), 7.04 (s, 2H), 6.39 (s, 1H), 5.33 (s, 1H), 2.47 (s, 3H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.6, 146.8, 139.5, 138.2, 137.6, 136.6, 129.7, 128.9, 128.7, 128.5, 127.5, 127.1, 126.4, 125.1, 124.6, 121.2, 66.8, 34.5, 30.2, 21.5; FT-IR (neat) 3628, 2958 cm−1; HRMS (ESI) m/z calcd for C30H34N3O [M + H]+ 452.2702, found 452.2683. 2,6-Di-tert-butyl-4-(3-(4-(tert-butyl)phenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6d): performed in 0.26 mmol scale of 5d; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (77 mg, 66% yield); mp = 226−228 °C; 1H NMR (400 MHz, CDCl3) δ 7.99−7.96 (m, 3H), 7.58 (d, J = 8.3 Hz, 2H), 7.51−7.45 (m, 1H), 7.41−7.37 (m, 2H), 7.00 (s, 2H), 6.37 (s, 1H), 5.30 (s, 1H), 1.40 (s, 9H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.6, 151.4, 146.9, 139.5, 137.7, 136.6, 128.9, 128.7, 128.6, 127.5, 126.9, 126.5, 126.0, 125.1, 124.6, 121.3, 66.8, 34.9, 34.5, 31.5, 30.2; FT-IR (neat) 3633, 2961 cm−1; HRMS (ESI) m/z calcd for C33H40N3O [M + H]+ 494.3171, found 494.3152. 2,6-Di-tert-butyl-4-(3-(2,4,5-trimethylphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6e): performed in 0.068 mmol scale of 5e; Rf = 0.5 (25% EtOAc in hexane); colorless gummy solid (16.6 mg, 51% yield); 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.3 Hz, 1H), 7.41−7.32 (m, 4H), 7.15 (s, 1H), 7.00 (s, 2H), 6.38 (s, 1H), 5.29 (s, 1H), 2.41 (s, 3H), 2.32 (s, 6H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.6, 146.8, 139.0, 138.7, 137.0, 136.6, 134.3, 134.1, 132.3, 131.1, 128.8, 128.4, 127.8, 127.5, 126.6, 124.9, 124.5, 121.3, 66.9, 34.5, 30.2, 19.8, 19.7, 19.4; FT-IR (neat) 3631, 2958 cm−1; HRMS (ESI) m/z calcd for C32H38N3O [M + H]+ 480.3015, found 480.3005. 2,6-Di-tert-butyl-4-(3-(4-methoxyphenyl)-8H-[1,2,3]triazolo[5,1a]isoindol-8-yl)phenol (6f): performed in 0.07 mmol scale of 5f; Rf = 0.4 (25% EtOAc in hexane); pale yellow solid (19.5 mg, 60% yield); mp = 218−220 °C; 1H NMR (400 MHz, CDCl3) δ 7.95−7.91 (m, 3H), 7.50−7.44 (m, 1H), 7.40−7.36 (m, 2H), 7.12−7.07 (m, 2H), 7.01 (s, 2H), 6.35 (s, 1H), 5.30 (s, 1H), 3.89 (s, 3H), 1.38 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 159.7, 154.6, 146.8, 139.3, 137.2, 136.6, 128.9, 128.5, 128.47, 127.5, 126.5, 125.1, 124.7, 124.2, 121.1, 114.5, 66.8, 55.5, 34.5, 30.2; FT-IR (neat) 3628, 2957 cm−1; HRMS (ESI) m/z calcd for C30H34N3O2 [M + H]+ 468.2651, found 468.2633. 2,6-Di-tert-butyl-4-(3-(4-methoxy-2-methylphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6g): performed in 0.068 mmol scale of 5g; Rf = 0.4 (25% EtOAc in hexane); yellow solid (15.4 mg, 46% yield); mp = 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 7.54− 7.51 (m, 2H), 7.41−7.33 (m, 3H), 7.00 (s, 2H), 6.92−6.87 (m, 2H), 6.38 (s, 1H), 5.29 (s, 1H), 3.88 (s, 3H), 2.47 (s, 3H), 1.38 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 159.8, 154.6, 146.8, 138.9, 138.7, 136.6, 131.1, 128.8, 128.4, 127.5, 126.6, 124.9, 124.5, 124.5, 123.1, 121.2, 116.3, 111.4, 66.9, 55.4, 34.5, 30.2, 20.8; FT-IR (neat) 3627, 8602

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

Note

The Journal of Organic Chemistry Hz), 114.2, 100.4 (d, JC−F = 15.5 Hz), 67.2, 34.5, 30.2; 19F NMR (376 MHz, CDCl3) δ −105.53; FT-IR (neat) 3629, 2957, 2232 cm−1; HRMS (ESI) m/z calcd for C30H30FN4O [M + H]+ 481.2404, found 481.2420. Methyl 4-(8-(3,5-Di-tert-butyl-4-hydroxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-3-yl)benzoate (6n): performed in 0.33 mmol scale of 5o; Rf = 0.3 (25% EtOAc in hexane); pale yellow solid (132 mg, 80% yield); mp = 186−188 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.53−7.49 (m, 1H), 7.45−7.39 (m, 2H), 7.01 (s, 2H), 6.38 (s, 1H), 5.32 (s, 1H), 3.96 (s, 3H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 167.0, 154.7, 147.0, 138.6, 138.5, 136.7, 136.1, 130.4, 129.6, 129.1, 129.07, 127.0, 126.96, 126.0, 125.3, 124.7, 121.4, 67.0, 52.4, 34.5, 30.2; FT-IR (neat) 3627, 2957, 1716 cm−1; HRMS (ESI) m/z calcd for C31H34N3O3 [M + H]+ 496.2600, found 496.2619. 2,6-Di-tert-butyl-4-(3-(6-methoxynaphthalen-2-yl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6o): performed in 0.063 mmol scale of 5i; Rf = 0.4 (25% EtOAc in hexane); pale yellow solid (22.7 mg, 70% yield); mp = 220−222 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 0.8 Hz, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.89−7.96 (m, 1H), 7.54−7.47 (m, 1H), 7.43−7.38 (m, 2H), 7.23−7.21 (m, 2H), 7.04 (s, 2H), 6.39 (s, 1H), 5.31 (s, 1H), 3.96 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 158.2, 154.7, 146.9, 139.7, 137.8, 136.7, 134.4, 129.9, 129.2, 129.0, 128.6, 127.6, 127.5, 126.8, 126.4, 126.0, 125.8, 125.2, 124.7, 121.2, 119.5, 105.9, 66.9, 55.5, 34.5, 30.2; FT-IR (neat) 3628, 2958 cm−1; HRMS (ESI) m/z calcd for C34H36N3O2 [M + H]+ 518.2808, found 518.2791. 2,6-Di-tert-butyl-4-(3-(pyren-1-yl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6p): performed in 0.057 mmol scale of 5q; Rf = 0.5 (25% EtOAc in hexane); pale yellow solid (15.8 mg, 50% yield); mp = 233−235 °C; 1H NMR (400 MHz, CDCl3) δ 8.46 (t, J = 9.5 Hz, 2H), 8.34 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 8.2 Hz, 2H), 8.16 (s, 2H), 8.13 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.39−7.35 (m, 2H), 7.32−7.29 (m, 1H), 7.13 (s, 2H), 6.53 (s, 1H), 5.34 (s, 1H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.7, 147.0, 139.8, 138.3, 136.8, 131.7, 131.6, 131.2, 128.9, 128.9, 128.7, 128.3, 128.1, 127.8, 127.6, 127.4, 126.5, 126.3, 125.9, 125.6, 125.4, 125.3, 125.1, 125.0, 124.9, 124.7, 124.7, 122.2, 67.2, 34.6, 30.3; FT-IR (neat) 3626, 2958, cm−1; HRMS (ESI) m/z calcd for C39H36N3O [M + H]+ 562.2858, found 562.2836. 2,6-Di-tert-butyl-4-(3-(phenanthren-9-yl)-8H-[1,2,3]triazolo[5,1a]isoindol-8-yl)phenol (6q): performed in 0.058 mmol scale of 5r; Rf = 0.5 (25% EtOAc in hexane); pale yellow solid (15.8 mg, 64% yield); mp = 223−225 °C; 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 8.3 Hz, 1H), 8.78 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.19 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.77−7.72 (m, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.65−7.60 (m, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.36 (td, J = 6.3, 2.2 Hz, 1H), 7.33−7.28 (m, 2H), 7.10 (s, 2H), 6.50 (s, 1H), 5.33 (s, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.7, 147.0, 139.8, 137.8, 136.8, 131.6, 131.0, 130.7, 130.2, 129.1, 129.0, 128.9, 128.7, 127.4, 127.3, 127.34, 127.1, 127.09, 127.0, 126.7, 126.4, 125.0, 124.7, 123.2, 122.8, 122.1, 67.2, 34.6, 30.3; FT-IR (neat) 3627, 2958 cm−1; HRMS (ESI) m/z calcd for C37H36N3O [M + H]+ 538.2858, found 538.2836. 2,6-Di-tert-butyl-4-(3-(thiophen-3-yl)-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6r): performed in 0.075 mmol scale of 5s; Rf = 0.4 (25% EtOAc in hexane); white solid (26.3 mg, 80% yield); mp = 197−199 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 1H), 7.84 (dd, J = 2.9, 1.2 Hz, 1H), 7.73 (dd, J = 5.0, 1.2 Hz, 1H), 7.51− 7.47 (m, 2H), 7.42−7.37 (m, 2H), 7.00 (s, 2H), 6.36 (s, 1H), 5.30 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.7, 146.8, 137.4, 136.7, 135.3, 132.5, 129.0, 128.6, 127.3, 126.9, 126.5, 126.3, 125.2, 124.6, 122.3, 121.2, 67.0, 34.5, 30.2; FT-IR (neat) 3631, 2958 cm−1; HRMS (ESI) m/z calcd for C27H30N3OS [M + H]+ 444.2110, found 444.2126. (8-(3,5-Di-tert-butyl-4-hydroxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-3-yl)methyl acetate (6s): performed in 0.38 mmol scale of 5p; Rf = 0.2 (25% EtOAc in hexane); white solid (134 mg, 81% yield); mp = 170−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.6

Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.39 (td, J = 7.7, 1 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 6.95 (s, 2H), 6.30 (s, 1H), 5.54 and 5.46 (ABq, JAB = 12.8 Hz, 2H), 5.30 (s, 1H), 2.13 (s, 3H), 1.36 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 171.0, 154.7, 146.7, 140.5, 136.7, 133.5, 129.1, 128.9, 126.8, 126.0, 124.9, 124.6, 122.3, 67.3, 57.8, 34.5, 30.2, 21.0; FT-IR (neat) 3629, 2959, 1741 cm−1; HRMS (ESI) m/z calcd for C26H32N3O3 [M + H]+ 434.2444, found 434.2428. 2,6-Di-tert-butyl-4-(3-(cyclohexylmethyl)-8H-[1,2,3]triazolo[5,1a]isoindol-8-yl)phenol (6t): performed in 0.064 mmol scale of 5t; Rf = 0.5 (25% EtOAc in hexane); white solid (17.7 mg, 60% yield); mp = 192−194 °C; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.6 Hz, 1H), 7.47−7.41 (m, 1H), 7.35−7.30 (m, 2H), 6.90 (s, 2H), 6.27 (s, 1H), 5.26 (s, 1H), 2.92−2.83 (m, 2H), 1.86−1.64 (m, 7H), 1.36 (s, 18H), 1.22−1.16 (m, 2H), 1.14−1.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 154.5, 146.8, 138.9, 138.1, 136.6, 128.8, 128.0, 127.7, 127.0, 125.0, 124.3, 120.8, 66.8, 39.1, 34.5, 33.8, 33.4, 33.3, 30.2, 26.6, 26.4, 26.3; FT-IR (neat) 3631, 2923 cm−1; HRMS (ESI) m/z calcd for C30H40N3O [M + H]+ 458.3171, found 458.3151. 2,6-Di-tert-butyl-4-(3-cyclohexyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6u): performed in 0.077 mmol scale of 5u; Rf = 0.5 (25% EtOAc in hexane); white solid (19.4 mg, 57% yield); mp = 192−194 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.48−7.42 (m, 1H), 7.32 (d, J = 4.1 Hz, 2H), 6.93 (s, 2H), 6.26 (s, 1H), 5.26 (s, 1H), 3.07 (tt, J = 12.0, 3.6 Hz, 1H), 2.12−2.09 (m, 2H), 1.94−1.90 (m, 2H), 1.83−1.71 (m, 4H), 1.53−1.47 (m, 2H), 1.36 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.5, 146.5, 144.8, 137.4, 136.5, 128.8, 127.9, 127.8, 126.8, 125.0, 124.5, 121.5, 66.7, 36.5, 34.5, 34.5, 32.9, 32.8, 30.2, 26.6, 26.2; FT-IR (neat) 3633, 2928 cm−1; HRMS (ESI) m/z calcd for C29H38N3O [M + H]+ 444.3015, found 444.3035. 2,6-Di-tert-butyl-4-(3-cyclopropyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6v): performed in 0.069 mmol scale of 8d; Rf = 0.4 (25% EtOAc in hexane); white solid (16.4 mg, 60% yield); mp = 182−184 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 1H), 7.49−7.42 (m, 1H), 7.35−7.30 (m, 2H), 6.95 (s, 2H), 6.25 (s, 1H), 5.27 (s, 1H), 2.21−2.14 (m, 1H), 1.37 (s, 18H), 1.16−1.07 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 154.5, 146.3, 140.9, 138.2, 136.6, 128.9, 127.9, 127.7, 126.6, 125.0, 124.6, 120.9, 66.9, 34.5, 30.2, 7.5, 7.4, 7.2; FT-IR (neat) 3629, 2957 cm−1; HRMS (ESI) m/z calcd for C26H32N3O [M + H]+ 402.2545, found 402.2527. 2,6-Dimethyl-4-(3-phenyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (6w): performed in 0.064 mmol scale of 8a; Rf = 0.3 (25% EtOAc in hexane); pale yellow gummy solid (9 mg, 40% yield); mp = 199−201 °C; 1H NMR (400 MHz, CDCl3) δ 8.02−8.00 (m, 2H), 7.95 (d, J = 7.7 Hz, 1H), 7.57−7.53 (m, 2H), 7.50−7.46 (m, 1H), 7.45−7.41 (m, 1H), 7.38 (dd, J = 7.4, 1.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 6.81 (s, 2H), 6.31 (s, 1H), 5.02 (s, 1H), 2.18 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.2, 147.1, 139.6, 138.0, 131.5, 129.1, 129.0, 128.9, 128.4, 128.1, 127.3, 127.2, 127.1, 125.0, 124.1, 121.3, 66.3, 16.2; FT-IR (neat) 3380, 2923 cm−1; HRMS (ESI) m/z calcd for C23H20N3O [M + H]+ 354.1606, found 354.1590. 2,6-Di-tert-butyl-4-(5-methyl-3-phenyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (8a): performed in 0.26 mmol scale of 7a; Rf = 0.5 (25% EtOAc in hexane); white solid (76 mg, 65% yield); mp = 185−187 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.4 Hz, 2H), 7.74 (s, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.27− 7.25 (m, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.01 (s, 2H), 6.33 (s, 1H), 5.29 (s, 1H), 2.48 (s, 3H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.6, 144.0, 139.3, 138.9, 137.9, 136.6, 131.7, 129.5, 129.1, 128.2, 127.4, 127.3, 126.6, 124.8, 124.6, 121.8, 66.7, 34.5, 30.2, 21.9; FT-IR (neat) 3630, 2958 cm−1; HRMS (ESI) m/z calcd for C30H34N3O [M + H]+ 452.2702, found 452.2720. 2,6-Di-tert-butyl-4-(6-methoxy-3-phenyl-8H-[1,2,3]triazolo[5,1a]isoindol-8-yl)phenol (8b): performed in 0.27 mmol scale of 7b; Rf = 0.4 (25% EtOAc in hexane); white solid (80 mg, 64% yield); mp = 187−180 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.7 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.01−6.98 (m, 3H), 6.90 (brs, 1H), 6.31 (s, 1H), 5.31 (s, 1H), 3.83 (s, 3H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 160.3, 154.7, 149.0, 138.3, 137.9, 136.7, 131.8, 129.0, 128.0, 127.0, 126.5, 8603

DOI: 10.1021/acs.joc.8b00573 J. Org. Chem. 2018, 83, 8596−8606

The Journal of Organic Chemistry

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124.6, 122.3, 120.1, 114.2, 111.3, 66.8, 55.8, 34.5, 30.2; FT-IR (neat) 3628, 2958 cm−1; HRMS (ESI) m/z calcd for C30H34N3O2 [M + H]+ 468.2651, found 468.2635. 2,6-Di-tert-butyl-4-(5,7-dimethoxy-3-phenyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (8c): performed in 0.065 mmol scale of 7c; Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (21.2 mg, 66% yield); mp = 231−233 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.02 (s, 2H), 6.47 (d, J = 1.9 Hz, 1H), 6.38 (s, 1H), 5.21 (s, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 1.37 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 162.2, 156.4, 154.1, 139.3, 137.8, 135.9, 131.7, 129.1, 129.0, 128.2, 127.3, 126.1, 125.7, 124.6, 98.9, 98.7, 65.3, 55.9, 55.7, 34.4, 30.3; FT-IR (neat) 3634, 2958 cm−1; HRMS (ESI) m/z calcd for C31H36N3O3 [M + H]+ 498.2757, found 498.2747. 2,6-Di-tert-butyl-4-(4,6-dimethoxy-3-phenyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (8d): performed in 0.043 mmol scale of 7d; Rf = 0.2 (5% EtOAc in hexane); white solid (13 mg, 60% yield); mp = 217−219 °C; 1H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 2H), 7.47−7.44 (m, 2H), 7.40−7.36 (m, 1H), 7.02 (s, 2H), 6.48 (s, 2H), 6.28 (s, 1H), 5.29 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 162.0, 154.8, 154.6, 149.7, 138.6, 136.6, 136.5, 131.9, 130.0, 127.7, 127.6, 126.7, 124.7, 110.0, 102.1, 98.6, 66.8, 55.9, 55.0, 34.5, 30.3; FT-IR (neat) 3628, 2959 cm−1; HRMS (ESI) m/z calcd for C31H36N3O3 [M + H]+ 498.2757, found 498.2746. 2,6-Di-tert-butyl-4-(7-fluoro-3-phenyl-8H-[1,2,3]triazolo[5,1-a]isoindol-8-yl)phenol (8e): performed in 0.058 mmol scale of 7e; Rf = 0.4 (25% EtOAc in hexane); white solid (15.8 mg, 60% yield); mp = 223−225 °C; 1H NMR (400 MHz, CDCl3) δ 7.99−7.97 (m, 2H), 7.92 (dd, J = 8.5, 4.8 Hz, 1H), 7.57−7.53 (m, 2H), 7.43 (tt, J = 6.9, 1.2 Hz, 1H), 7.19 (td, J = 8.8, 2.4 Hz, 1H), 7.09 (dd, J = 8.2, 1.9 Hz, 1H), 6.98 (s, 2H), 6.35 (s, 1H), 5.33 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, JC−F = 247.0 Hz), 154.9, 149.4 (d, JC−F = 8.5 Hz), 139.1, 137.1, 136.9, 131.4, 129.1, 128.4, 127.1, 125.8, 124.5, 123.5 (d, JC−F = 2.9 Hz), 122.7 (d, JC−F = 8.9 Hz), 116.2 (d, JC−F = 23.0 Hz), 113.1 (d, JC−F = 24.4 Hz), 66.9 (d, JC−F = 2.7 Hz), 34.5, 30.2; 19F NMR (376 MHz, CDCl3) δ −110.67; FT-IR (neat) 3631, 2958 cm−1; HRMS (ESI) m/z calcd for C29H31FN3O [M + H]+ 456.2451, found 456.2435. 4-(Azido(2-(phenylethynyl)phenyl)methyl)-2,6-di-tert-butylphenol (10). A mixture of 5a (0.063 mmol), Me3SiN3 (0.19 mmol), and AgSbF6 (0.0063 mmol) in CDCl3 (1 mL) was stirred in a closed vial under an inert atmosphere at 45 °C until 5a was completely consumed (ca. 45 min), and the crude material was directly analyzed using 1H and 13C NMR techniques. In this case, quantitative conversion of 5a to 10 was observed: Rf = 0.5 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.55−7.49 (m, 4H), 7.41−7.34 (m, 4H), 7.31−7.26 (m, 1H), 7.17 (s, 2H), 6.28 (s, 1H), 5.19 (s, 1H), 1.36 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.6, 142.3, 136.0, 132.5, 131.7, 129.8, 128.9, 128.7, 128.5, 127.7, 126.8, 124.3, 123.1, 122.1, 95.0, 87.4, 66.9, 34.5, 30.3; FT-IR (neat) 3627, 2959, 2090 cm−1 (IR spectrum was recorded after removal of the solvent and excess Me3SiN3 under reduced pressure); HRMS (ESI) m/z calcd for C29H32N3O [M + H]+ 438.2545, found 438.2532. 4-(Azido(4-(phenylethynyl)phenyl)methyl)-2,6-di-tert-butylphenol (13). A mixture of 2,6-di-tert-butyl-4-(4-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (5x)18b (0.063 mmol), Me3SiN3 (0.19 mmol), and CuOTf·toluene (0.0063 mmol) in DCE (1 mL) was stirred in a closed vial under an inert atmosphere at 60 °C for 24 h. After the removal of solvent and excess Me3SiN3 under reduced pressure, the crude material was directly analyzed using 1H and 13C NMR techniques. In this case, quantitative conversion of 5x to 13 was observed: Rf = 0.5 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.62−7.60 (m, 1H), 7.55−7.52 (m, 3H), 7.38−7.32 (m, 5H), 7.06 (s, 2H), 5.65 (s, 1H), 5.26 (s, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.8, 140.4, 136.2, 132.0, 131.9, 131.8, 131.7, 130.5, 129.9, 128.5, 127.4, 124.4, 123.3, 122.8, 89.9, 89.2, 68.9, 34.5, 30.3; FT-IR (neat) 3630, 2959, 2130, 2098 cm−1; HRMS (ESI) m/z calcd for C29H32NO [M−N2 + H]+ 410.2484, found 410.2467.

Note

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00573. 1 H, 13C, and 19F spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ramasamy Vijaya Anand: 0000-0001-9490-4569 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge DST-SERB (EMR/2015/ 001759) for the financial support and IISER Mohali for the infrastructure. A.S.J. and Y.A.P. thank IISER Mohali for research fellowships. The authors also acknowledge the NMR and HRMS facilities at IISER Mohali.

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REFERENCES

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The Journal of Organic Chemistry

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(20) Interestingly, the O-silylated products were not observed in any of the cases. In fact, this was the case in our earlier study as well (ref 18d). We believe that the sterically bulky t-Bu substituents shied the phenolate anion from the reaction with bulky trimethylsilyl group. So, we assume that the phenolate anion picks up a proton either from the moisture present in the solvent or after the aqueous workup. (21) Uno, T.; Yamamoto, S.; Yamane, A.; Kubo, M.; Itoh, T. Asymmetric Anionic Polymerizations of 7-(o-Substituted-phenyl)-2,6Dimethyl-1,4-Benzoquinone Methides: Electrostatic Interaction and Steric, Inductive, and Resonance Effects of the ortho-Substituent on the Optical Activity. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 1048−1058.

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