Catalyzed 1,6-Conjugate Addition of Me3SiN3 to

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A Tandem One-pot Approach to Access 1,2,3-Triazole-fused Isoindolines through Cu-Catalyzed 1,6-Conjugate Addition of Me3SiN3 to pQuinone Methides followed by Intramolecular Click Cycloaddition Abhijeet S Jadhav, Yogesh A Pankhade, and Ramasamy Vijaya Anand J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00573 • Publication Date (Web): 23 May 2018 Downloaded from http://pubs.acs.org on May 23, 2018

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The Journal of Organic Chemistry

A Tandem One-pot Approach to Access 1,2,3-Triazole-fused Isoindolines through CuCatalyzed 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*

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, Knowledge City, S. A. S. Nagar, Manauli (PO), Punjab –140306. India. E-mail: [email protected]

O R3

R3 CuOTf.toluene (10 mol %) TMS-N3 (3 equiv.)

R1

R1 N N N

DCE, 60 oC R2 R1

OH

R3

R3

= H, alkyl, O-alkyl, halo, etc. R 2 = alkyl, aryl 3 R = tBu, Me

R2 27 examples up to 89% yield

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. Over 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 Especially, 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

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biologically significant molecules.3 Moreover, these heterocycles also found diverse range of applications in 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 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 “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 catalysed versions, in the recent past, several organocatalytic methods9 have been developed based on 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 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 & 2 exhibit remarkable anti-cancer activities (Fig. 1).11 The sugar based fused 1,2,3-triazole derivative 3 showed interesting biological response towards α-glucosidase enzyme.12 The morpholine-derived triazole derivative 4 was found to have potential activity against Alzheimer disease (Fig. 1).13

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


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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 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.

Scheme 1. Major pathways to access 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 unique 1,6-reactivity profile toward various nucleophiles.17 While exploring the p-QMs as 1,6-acceptors to prepare unsymmetrical diaryland triarylmethane derivatives,18 we thought of utilizing this chemistry to synthesize fused 1,2,3-triazole derivatives. Consequently, we have developed an unprecedented tandem onepot approach to access 1,2,3-triazole-fused isoindolines through a Cu(I)-catalyzed 1,6conjugate addition of azides to o-alkynylated p-QMs 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 by treating 5a with Me3SiN3 under various reaction



O R1

O R1

R1 PdCl 2(PPh 3) 2 (5 mol %) CuI (5 mol %)

R2

R3

+ Br

Page 4 of 43

Et 3N, 70 oC

R1

R2

R 3 = aryl, alkyl

R1 = tBu, Me R 2 = alkyl, alkoxy, halo, etc.

R3 5a-w and 7a-e 48-92% yields

Scheme 2. General scheme for the synthesis of 2-alkynylated p-QMs

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 oC (entries 1 & 2). But, 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 oC in DCE; however, 6a was observed in traces and 27 % yield, respectively (entries 5 & 6). In the case 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 Ag- and Au-based salts. Although all 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 CuOTf·toluene complex as a catalyst (entries 13 – 15). However, the isolated yields of 6a in those cases were inferior when compared that of the reaction in DCE (entry 8). Due to its volatile nature, 3 equivalents of Me3SiN3 with respect to 5a was used in all the optimization experiments (entries 1-15) to drive the reaction to completion, as lowering the amount of


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Me3SiN3 to 2 equivalents significantly reduced the yield of 6a (entry 16). No product formation was observed when NaN3 was used instead of Me3SiN3 (entry 17). Table 1. Optimization studies O tBu

HO

tBu

Me 3SiN3 (3 equiv.) catalyst (10 mol %)

tBu

tBu

N

N

N

solvent Ph 5a

Ph

6a

entry

catalyst

solvent

temp (oC)

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 of 5a and 0.152 mmol of Me3SiN3 in solvent (1.5 mL). b 11% mol % of 2,2’-bipyridyl has been used as a ligand. c 2 equiv. of Me3SiN3 was used. d NaN3 was used instead of Me3SiN3. NR = no reaction. rt = room temperature

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 hindered substituents at the alkyne part (5p & 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. Table 2. Substrate scope with different 2-alkynylated p-QMsa O R1

R1

R1

HO R1

TMS-N3 (3 equiv) CuOTf.PhMe (10 mol %)

N

DCE, 60 oC

N

N R

6b-w

5b-w R ---------------------------------------------------------------------------------------------------------------------------tBu tBu tBu HO HO HO tBu

tBu

N

N

N

N

N

tBu

N

N

N

N

X 6b, X = 4-Ph, 20 h, 65% 6o, 20h, 70% 6p, 36 h, 50% OMe 6c, X = 4-Me, 30 h, 63%b tBu tBu 6d, X = 4-tBu, 30 h, 66%b HO HO 6e, X = 2,4,5-trimethyl, 25 h, 51% tBu 6f, X = 4-OMe, 25 h, 60% tBu N 6g, X = 2-Me; 4-OMe, 25 h, 46% N N N N N 6h, X = 4-OPh, 25 h, 53% 6i, X = 2-Cl, 20 h, 64% 6j, X = 3-F, 30 h, 82% b S 6k, X = 2-CF3, 20 h, 75% b 6q, 36 h, 64% 6l, X = 4-CN,15 h, 80% 6r, 15 h, 80% 6m, X = 3-F; 4-CN, 15 h, 77% 6n, X = 4-COOMe, 24 h, 80%b tBu HO Me HO tBu HO tBu Me N tBu N N N N N N N N R Ph OAc 6t, R = CH2-cyclohexyl, 25 h, 60% 6u, R = cyclohexyl, 25 h, 57% 6w, 36 h, 40% 6s, 24 h, 81% b 6v, R = cyclopropyl, 25 h, 60%

a

Most of the reactions were carried out with 0.04 – 0.08 mmol scale of 5. b Reactions were carried out with 0.26 – 0.38 mmol scale of 5 and the details can be found in the experimental section.

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 p-QMs, and the results are presented in Table 3. In general, the p-QMs 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.


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Table 3. Substrate scopea O tBu

tBu

HO

tBu

tBu

TMS-N3 (3 equiv) CuOTf.PhMe (10 mol %)

N

N

N

DCE, 60 oC

R

Ph R

Ph 7a-e

8a-e

-------------------------------------------------------------------------------------------------------------------------

HO

tBu

tBu

HO

tBu

tBu

tBu

N

N

tBu

HO

N

N

N

N

N

N

N

MeO MeO

HO

tBu

HO

tBu

tBu

tBu

N

MeO

MeO 8c, 20 h, 66%

8b, 36 h, 64%b

8a, 36 h, 65%b

N

N

N

OMe 8d, 12 h, 60%

N

N

F 8e, 18 h, 60%

a

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

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 decreasing over a period of time, and at the same, the intensity of 6a was increasing gradually. This clearly indicates that the new spot indeed 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 NMR tube using 10 mol% of AgSbF6 (entry 9, Table 1)19 at 45 oC for 45 min and the crude



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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 ppm and 5.19 ppm, which correspond to the benzylic proton and the phenolic -OH proton,20 respectively (please refer SI 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

13

C NMR

spectroscopic analysis (signals at 94.9 and 87.4 ppm for alkyne) and IR spectroscopic analysis (strong band at 2090 cm-1 for azido group). To confirm the involvement of 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 confirms the presence of azide (2098 cm-1) and alkyne (2130 cm-1) functionalities. Interestingly, 13 was observed as sole product, and the other possible 1,2,3triazole product was not at all observed. Based on these observations, one can unambiguously confirm that the reaction is actually proceeding through Path A (Scheme 3), i.e., via the azide intermediate 10.


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tBu

Path A TMS-N3 [Cu] 1,6-addition

HO

N N N

tBu

[Cu]

6a

Ph

10 confirmed by NMR & IR tBu

5a

Path B TMS-N3 [Cu] 'click'

O N N

tBu

[Cu] N

6a

Ph 11 not observed in NMR & IR -----------------------------------------------------------------------------------------------O OH tBu tBu tBu tBu [Cu], TMS-N3 DCE, 60 oC

N3

12 Ph

Ph

13 confirmed by NMR & IR

Scheme 3. Control experiments for mechanistic studies 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-triazole-fused 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 similar kind of biological activities and find some suitable therapeutic applications in near future. Experimental Section General Information All reactions were carried out under argon atmosphere employing flame-dried glass wares. Most of the reagents and starting materials were purchased from commercial sources and used as such.

All 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 SMP20 melting point apparatus and are uncorrected. 1H,

13

C and

19

F spectra

were recorded in CDCl3 (400, 100 and 376 MHz respectively) on Bruker FT-NMR



Page 10 of 43

spectrometer. Chemical shift (δ) values are reported in parts per million (ppm) relative to TMS and the coupling constants (J) are reported in Hz. High resolution mass spectra were recorded on 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 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 p-quinone methides (5a-w and 7ae): 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). Organic layer was separated and the aqueous layer was extracted with CH2Cl2 (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, 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-2,5-dienone (5a) Rf = 0.6 (5% EtOAc in hexane); yellow solid (290 mg, 91% yield); m. p. = 140-142 ºC; 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);

13

C 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.


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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); m. p. = 127-129 ºC; 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (m, 1H), 7.63-7.61 (m, 4H), 7.60-7.57 (m, 3H), 7.507.44 (m, 5H), 7.43-7.37 (m, 2H), 7.14 (s, 1H), 1.40 (s, 9H), 1.31 (s, 9H);

13

C 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-2,5-dienone (5c) Rf = 0.6 (5% EtOAc in hexane); orange solid (254 mg, 77% yield); m. p. = 148-150 ºC; 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);

13

C

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); m. p. = 85-87 ºC; 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 cm1

; 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); m. p. = 125-127 ºC; 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);

13

C 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); m. p. = 139-141 ºC; 1H NMR (400 MHz, CDCl3) δ 7.64-7.59 (m, 1H), 7.53 (s, 1H), 7.46-7.42 (m, 4H), 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-2,5dienone (5g) Rf = 0.4 (5% EtOAc in hexane); orange solid (288 mg, 81% yield); m. p. = 166-168 ºC; 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,


Page 12 of 43

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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)

13

C 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); m. p. = 130-132 ºC; 1H NMR (400 MHz, CDCl3) δ 7.71-7.67 (m, 2H), 7.57-7.55 (m, 1H), 7.52-7.50 (m, 1H), 7.467.38 (m, 4H), 7.31-7.24 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 1.35 (s, 9H), 1.28 (s, 9H);

13

C

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)



Page 14 of 43

Rf = 0.6 (5% EtOAc in hexane); yellow solid (211 mg, 63% yield); m. p. = 128-130 ºC; 1H NMR (400 MHz, CDCl3) δ 7.65-7.63 (m, 1H), 7.49-7.46 (m, 2H), 7.44-7.38 (m, 3H), 7.357.28 (m, 2H), 7.21-7.18 (m, 1H), 7.09-7.04 (m, 2H), 1.36 (s, 9H), 1.26 (s, 9H);

13

C 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-2,5dienone (5k) Rf = 0.6 (5% EtOAc in hexane); yellow solid (235 mg, 63% yield); m. p. = 122-124 ºC; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.8 Hz 1H), 7.68-7.65 (m, 2H), 7.61 (s, 1H), 7.557.50 (m, 2H), 7.47-7.38 (m, 4H), 7.15 (d, J = 1.8 Hz 1H), 1.36 (s, 9H), 1.28 (s, 9H);

13

C

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); m. p. = 194-196 ºC; 1H NMR (400 MHz, CDCl3) δ 7.66-7.63 (m, 3H), 7.57-7.54 (m, 2H), 7.48-7.47 (m, 2H), 7.447.38 (m, 3H), 7.07 (d, J = 2.3 Hz, 1H), 1.35 (s, 9H), 1.24 (s, 9H);


13

C NMR (100 MHz,

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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)-2fluorobenzonitrile (5m) Rf = 0.2 (5% EtOAc in hexane); orange solid (210 mg, 60% yield); m. p. = 197-199 ºC; 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, JCF

= 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-1

ylidene)methyl)phenyl)

ethynyl) benzoate (5n) Rf = 0.3 (5% EtOAc in hexane); yellow solid (200 mg, 55% yield); m. p. = 159-161 ºC; 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);

13

C 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-2,5dienone (5o) Rf = 0.1 (5% EtOAc in hexane); orange solid (240 mg, 62% yield); m. p. = 148-150 ºC; 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);

13

C 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)cyclohexa-2,5-dienone (5p) Rf = 0.3 (5% EtOAc in hexane); orange solid (320 mg, 71% yield); m. p. = 178-180 ºC; 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);

13

C 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,


Page 16 of 43

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4H), 7.19 (d, J = 2.2 Hz, 1H), 1.39 (s, 9H), 1.30 (s, 9H);

13


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); m. p.= 127-129 ºC 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), 7.337.31 (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, 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);

13

C 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)



Page 18 of 43

Rf = 0.7 (5% EtOAc in hexane); orange solid (217 mg, 66% yield); m. p. = 87-89 ºC; 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), 1.701.53 (m, 3H), 1.34 (s, 9H), 1.28 (s, 9H), 1.21-1.14 (m, 2H), 1.12-1.05 (m, 2H);

13

C 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)cyclohexa-2,5-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.


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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)-2,6dimethylphenol22 (0.23 g, 0.79 mmol) in hexanes (25 mL) under inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. The aqueous layer was separated and extracted with hexanes (50 mL x 2). The combined organic layers 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)-2,6dimethylcyclohexa-2,5-dienone (0.21 g, 92% yield) as a yellow solid; Rf = 0.4 (10% EtOAc in hexane); m. p. = 108-110 ℃; 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); 13

C 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) The reaction was 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, 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; FT-IR (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); m. p. = 153-155 ºC; 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);

13

C 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); m. p.=149-151 ºC 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);

13

C 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.


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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); m. p. = 172-174 ºC; 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); m. p. = 132-134 ºC; 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;

19

F 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-v and 8a-e): A mixture of 2-alkynylated p-quinone methide (0.5 mmol), TMSN3 (1.5 mmol) and CuOTf·toluene (0.05 mmol) in DCE (5 mL) stirred in a closed vial under inert atmosphere at 60 ℃ temperature 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 and eluted using EtOAc/hexane mixture to obtain 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-8-yl)phenol (6a) The reaction was performed in 0.063 mmol scale of 5a; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (23.3 mg, 85% yield); m. p. = 201-203 ºC; 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) The reaction was performed in 0.053 mmol scale of 5b; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (17.6 mg, 65% yield); m. p. = 219-221 ºC; 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-8-yl)phenol (6c)


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The reaction was performed in 0.28 mmol scale of 5c; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (90 mg, 63% yield); m. p. = 198-200 ºC; 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) The reaction was performed in 0.26 mmol scale of 5d; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (77 mg, 66% yield); m. p. = 226-228 ºC; 1H NMR (400 MHz, CDCl3) δ 7.997.96 (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-8yl)phenol (6e) The reaction was performed in 0.068 mmol scale of 5e; Rf = 0.5 (25% EtOAc in hexane); colourless 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[5,1-a]isoindol-8-yl)phenol (6f) The reaction was performed in 0.07 mmol scale of 5f; Rf = 0.4 (25% EtOAc in hexane); pale yellow solid (19.5 mg, 60% yield); m. p. = 218-220 ºC; 1H NMR (400 MHz, CDCl3) δ 7.957.91 (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); 13C 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-8yl)phenol (6g) The reaction was performed in 0.068 mmol scale of 5g; Rf = 0.4 (25% EtOAc in hexane); yellow solid (15.4 mg, 46% yield); m. p. = 120-122 ºC; 1H NMR (400 MHz, CDCl3) δ 7.547.51 (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); 13C 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, 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[5,1-a]isoindol-8-yl)phenol (6h)


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The reaction was performed in 0.051 mmol scale of 5h; Rf = 0.5 (25% EtOAc in hexane); pale yellow solid (14.3 mg, 53% yield); m. p. = 180-182 ºC; 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) The reaction was performed in 0.058 mmol scale of 5j; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (17.4 mg, 64% yield); m. p. = 202-204 ºC; 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) The reaction was performed in 0.27 mmol scale of 5k; Rf = 0.6 (25% EtOAc in hexane); pale yellow solid (100.3 mg, 82% yield); m. p. = 209-211 ºC; 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;

19

Page 26 of 43

F 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-8yl)phenol (6k) The reaction was performed in 0.28 mmol scale of 5l; Rf = 0.4 (25% EtOAc in hexane); pale yellow solid (107 mg, 75% yield); m. p. = 172-174 ºC; 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);

13

C 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[5,1-a]isoindol-3-yl) benzonitrile (6l) The reaction was performed in 0.071 mmol scale of 5m; Rf = 0.4 (25% EtOAc in hexane); white solid (26.5 mg, 80% yield); m. p. = 261-263 ºC; 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), 7.487.41 (m, 2H), 7.01 (s, 2H), 6.40 (s, 1H), 5.33 (s, 1H), 1.38 (s, 18H);

13

C 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.


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4-(8-(3,5-di-tert-butyl-4-hydroxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindol-3-yl)-2fluorobenzonitrile (6m) The reaction was performed in 0.057 mmol scale of 5n; Rf = 0.4 (25% EtOAc in hexane); white solid (21 mg, 77% yield); m. p. = 234-236 ºC; 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 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 cm1

; 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) The reaction was performed in 0.33 mmol scale of 5o; Rf = 0.3 (25% EtOAc in hexane); pale yellow solid (132 mg, 80% yield); m. p. = 186-188 ºC; 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), 7.457.39 (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-8yl)phenol (6o)



The reaction was performed in 0.063 mmol scale of 5i; Rf = 0.4 (25% EtOAc in hexane); pale yellow solid (22.7 mg, 70% yield); m. p. = 220-222 ºC; 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) The reaction was performed in 0.057 mmol scale of 5q; Rf = 0.5 (25% EtOAc in hexane); pale yellow solid (15.8 mg, 50% yield); m. p. = 233-235 ºC; 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[5,1-a]isoindol-8-yl)phenol (6q) The reaction was performed in 0.058 mmol scale of 5r; Rf = 0.5 (25% EtOAc in hexane); pale yellow solid (15.8 mg, 64% yield); m. p. = 223-225 ºC; 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


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= 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);

13

C 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) The reaction was performed in 0.075 mmol scale of 5s; Rf = 0.4 (25% EtOAc in hexane); white solid (26.3 mg, 80% yield); m. p. = 197-199 ºC; 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) The reaction was performed in 0.38 mmol scale of 5p; Rf = 0.2 (25% EtOAc in hexane); white solid (134 mg, 81% yield); m. p. = 170-172 ºC; 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[5,1-a]isoindol-8-yl)phenol (6t) The reaction was performed in 0.064 mmol scale of 5t; Rf = 0.5 (25% EtOAc in hexane); white solid (17.7 mg, 60% yield); m. p. = 192-194 ºC; 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) The reaction was performed in 0.077 mmol scale of 5u; Rf = 0.5 (25% EtOAc in hexane); white solid (19.4 mg, 57% yield); m. p. = 192-194 ºC; 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);

13

C 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) The reaction was performed in 0.069 mmol scale of 8d; Rf = 0.4 (25% EtOAc in hexane); white solid (16.4 mg, 60% yield); m. p. = 182-184 ºC; 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,


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1H), 2.21-2.14 (m, 1H), 1.37 (s, 18H), 1.16-1.07 (m, 4H);

13


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) The reaction was performed in 0.064 mmol scale of 8a; Rf = 0.3 (25% EtOAc in hexane); pale yellow gummy solid (9 mg, 40% yield); m. p. = 199-201 ℃; 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) The reaction was performed in 0.26 mmol scale of 7a; Rf = 0.5 (25% EtOAc in hexane); white solid (76 mg, 65% yield); m. p. = 185-187 ºC; 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[5,1-a]isoindol-8-yl)phenol (8b) The reaction was performed in 0.27 mmol scale of 7b; Rf = 0.4 (25% EtOAc in hexane); white solid (80 mg, 64% yield); m. p. = 187-180 ºC; 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, 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) The reaction was performed in 0.065 mmol scale of 7c; Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (21.2 mg, 66% yield); m. p. = 231-233 ºC; 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) The reaction was performed in 0.043 mmol scale of 7d; Rf = 0.2 (5% EtOAc in hexane); white solid (13 mg, 60% yield); m. p. = 217-219 ºC; 1H NMR (400 MHz, CDCl3) δ 7.88-7.86


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(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) The reaction was performed in 0.058 mmol scale of 7e; Rf = 0.4 (25% EtOAc in hexane); white solid (15.8 mg, 60% yield); m. p. = 223-225 ºC; 1H NMR (400 MHz, CDCl3) δ 7.997.97 (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);

13

C 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 inert atmosphere at 45 ºC temperature until 5a was completely consumed (ca 45 min) and the crude was directly analyzed using 1H and

13

C

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);

13

C 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 inert atmosphere at 60 ºC temperature for 24 h. After the removal of solvent and excess Me3SiN3 under reduced pressure, the crude 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. Acknowledgements The authors gratefully acknowledge DST-SERB (EMR/2015/001759) for the financial support and IISER Mohali for the infrastructure. ASJ and YAP thank IISER Mohali for research fellowships. The authors also acknowledge the NMR and HRMS facilities at IISER Mohali.

Supporting Information 1

H, 13C and 19F spectra of all new compounds.


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Notes

The Authors declare no competing financial interest. References 1. For selected reviews, see (a) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Click Chemistry: 1,2,3‐Triazoles as Pharmacophores. Chem. Asian J. 2011, 6, 2696-2718. (b) El-Sagheer, A. H.; Brown, T. Click Nucleic Acid Ligation: Applications in Biology and Nanotechnology. Acc. Chem. Res. 2012, 45, 1258-1267. (c) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click Chemistry for Drug Development and Diverse Chemical–Biology Applications. Chem. Rev. 2013, 113, 4905-4979. (d) Bonandi, E.; Christodoulou, M. S.; Fumagalli, G.; Perdicchia, D.; Rastelli, G.; Passarella, D. The 1,2,3-Triazole Ring as a Bioisostere in Medicinal Chemistry. Drug Discov. Today 2017, 22, 1572-1581. (e) Dheer, D.; Singh, V.; Shankar, R. Medicinal Attributes of 1,2,3-Triazoles: Current Developments. Bioorg. Chem. 2017, 71, 30-54 and references cited therein. 2. For selected reviews, see (a) Muller, T.; Bräse, S. Click Chemistry Finds Its Way into Covalent Porous Organic Materials. Angew. Chem. Int. Ed. 2011, 50, 11844-11845. (b) Lau, Y. H.; Rutledge, P. J.; Watkinson, M.; Todd, M. H. Chemical Sensors that Incorporate Click-Derived Triazoles. Chem. Soc. Rev. 2011, 40, 2848-2866. (c) Chu, C.; Liu, R. Application of Click Chemistry on Preparation of Separation Materials for Liquid Chromatography. Chem. Soc. Rev. 2011, 40, 2177-2188. (d) Astruc, D.; Liang, L.; Rapakousiou, A; Ruiz, J. Click Dendrimers and Triazole-Related Aspects: Catalysts, Mechanism, Synthesis, and Functions. A Bridge between Dendritic Architectures and Nanomaterials. Acc. Chem. Res. 2012, 45, 630-640. (e) Xi, W.; Scott, T. F.; Kloxin, C. J.; Bowman, C. N Click Chemistry in Materials Science. Adv.



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Funct. Mater. 2014, 24, 2572-2590. (f) Huo, J.; Hu, H.; Zhang, M.; Hu, X.; Chen, M.; Chen, D.; Liu, J.; Xiao, G.; Wang, Y.; Wen, Z. A Mini Review of the Synthesis of Poly-1,2,3-Triazole-Based Functional Materials. RSC Adv. 2017, 7, 2281-2287 and references cited therein. 3. (a) Kolb, H. C.; Sharpless, K. B. The Growing Impact of Click Chemistry on Drug Discovery. Drug Discover. Today 2003, 8, 1128-1137. (b) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R. Heterocyclic Peptide Backbone Modifications in an αHelical Coiled Coil. J. Am. Chem. Soc. 2004, 126, 15366-15367. (c) Mohammed, I.; Kummetha, I. R.; Singh, G.; Sharova, N.; Lichinchi, G.; Dang, J.; Stevenson, M.; Rana, T. M. 1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif Antagonists. J. Med. Chem. 2016, 59, 7677-7682. 4. Fan, W. -Q.; Katritzky, A. R. In Comprehensive Heterocyclic Chemistry II, Katritzky, A.; Rees, C. W.; Scriven, E. F. V. Eds.; Elsevier: Oxford, 1996; Vol. 4, p 1. 5. (a) Huisgen, R.; Szeimies, G.; Möbius, L. 1.3‐Dipolare Cycloadditionen, XXXII. Kinetik der Additionen organischer Azide an CC‐Mehrfachbindungen. Chem. Ber. 1967, 100, 2494-2507. (b) Huisgen, R. Kinetics and Reaction Mechanisms: Selected Examples from the Experience of Forty Years. Pure Appl. Chem. 1989, 61, 613-628. 6. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40, 2004-2021. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition Process: Copper(I)‐Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596-2599. 7. (a) Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles

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(b) Meldal, M.; Tornøe, C. W. Cu-Catalyzed Azide−Alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952-3015. 8. For selected reviews and recent examples: (a) Moses, J. E.; Moorhouse, A. D. The Growing Applications of Click Chemistry. Chem. Soc. Rev. 2007, 36, 1249-1262. (b) Amblard, F.; Cho, J. H.; Schinazi, R. F. Cu(I)-Catalyzed Huisgen Azide−Alkyne 1,3Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry. Chem. Rev. 2009, 109, 4207-4220. (c) Becer, C. R.; Hoogenboom, R.; Schubert, U. S. Click Chemistry Beyond Metal‐Catalyzed Cycloaddition. Angew. Chem. Int. Ed. 2009, 48, 4900-4908. (d) Castro, V.; Rodríguez, H.; Albericio, F. CuAAC: An Efficient Click Chemistry Reaction on Solid Phase. ACS Comb. Sci. 2016, 18, 1-14. (e) Tiwari, V. K.; Mishra, B. B.; Mishra, K. B.; Mishra, N.; Singh, A. S.; Chen, X. Cu-Catalyzed Click Reaction in Carbohydrate Chemistry. Chem. Rev. 2016, 116, 3086-3240. (f) Kacprzak, K.; Skiera, I.; Piasecka, M.; Paryzek, Z. Alkaloids and Isoprenoids Modification by Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddition

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(a) Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. Amino Acid‐Catalyzed Cascade [3+2]‐Cycloaddition/Hydrolysis Reactions Based on the Push–Pull Dienamine Platform: Synthesis of Highly Functionalized NH‐1,2,3‐Triazoles. Chem.



Eur. J. 2008, 14, 9143-9147. (b) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Organocatalytic Enamide–Azide Cycloaddition Reactions: Regiospecific Synthesis of 1,4,5‐Trisubstituted‐1,2,3‐Triazoles. Chem. Eur. J. 2011, 17, 3584-3587. (c) Belkheria, M.; Abed, D. E.; Pons, J. -M.; Bressy, C. Organocatalytic Synthesis of 1,2,3‐Triazoles from Unactivated Ketones and Arylazides. Chem. Eur. J. 2011, 17, 12917-12921.

(d) For a highlight, see: Ramasastry, S. S. V. Enamine/Enolate‐

Mediated Organocatalytic Azide–Carbonyl [3+2] Cycloaddition Reactions for the Synthesis of Densely Functionalized 1,2,3‐Triazoles. Angew. Chem. Int. Ed. 2014, 53, 14310-14312. (e) For a recent review, see: John, J.; Thomas, J.; Dehaen, W. Organocatalytic Routes Toward Substituted 1,2,3-Triazoles. Chem. Commun. 2015, 51, 10797-10806 and references cited therein. 10. L´Abbe, G. Dimroth Reaction. Ind. Chim. Belge 1971, 36, 3-10 [CA 74, 99917 (1971)]. 11. (a) Narsimha, S.; Battula, K. S.; Nukala, S. K.; Gondru, R.; Reddy, Y. N.; Nagavelli, V. R. One-Pot Synthesis of Fused Benzoxazino[1,2,3]triazolyl[4,5-c]quinolinone Derivatives and Their Anticancer Activity. RSC Adv. 2016, 6, 74332-74339. (b) Antonini, I.; Santoni, G.; Lucciarini, R.; Amantini, C.; Sparapani, S.; Magnano, A. Synthesis and Biological Evaluation of New Asymmetrical Bisintercalators as Potential Antitumor Drugs. J. Med. Chem. 2006, 49, 7198-7207. 12. Mishra, K. B.; Shashi, S.; Tiwari, V. K. Metal Free Synthesis of Morpholine Fused [5,1-c] Triazolyl Glycoconjugates via Glycosyl Azido Alcohols. RSC Adv. 2015, 5, 86840-86848. 13. Whittaker, B.; Steele, C.; Hardick, D.; Dale, M.; Pomel, V.; Quattropani, A.; Beher, D. Fused Triazole Derivatives as Gamma Secretase Modulators. Eur. Pat. Appl. 2014, EP 2687528 A1.


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14. For selected examples: (a) Choudhury, C.; Mandal, S. B.; Achari, B. Palladium– Copper Catalysed Heteroannulation of Acetylenic Compounds: An Expeditious Synthesis of Isoindoline Fused with Triazoles. Tetrahedron Lett. 2005, 46, 8531-8534. (b) Pirali, T.; Tron, G. C.; Zhu, J. One-Pot Synthesis of Macrocycles by a Tandem Three-Component Reaction and Intramolecular [3+2] Cycloaddition. Org. Lett. 2006, 8, 4145-4148. (c) Mohapatra, D. K.; Maity, P. K.; Gonnade, R. G.; Chorghade, M. S.; Gurjar, M. K. Synthesis of New Chiral 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5a]pyrazines from α-Amino Acid Derivatives under Mild Conditions. Synlett 2007, 1893-1896. (d) Declerck, V.; Toupet, L.; Martinez, J.; Lamaty, F. Selective [3+2] Huisgen Cycloaddition. Synthesis of Trans-Disubstituted Triazolodiazepines from Aza-Baylis−Hillman Adducts. J. Org. Chem. 2009, 74, 2004-2007. (e) Sudhir, V. S.; Kumar, N. Y. P.; Baig, R. B. N.; Chandrasekaran, S. Facile Entry into Triazole Fused Heterocycles via Sulfamidate Derived Azido-alkynes. J. Org. Chem. 2009, 74, 75887591. (f) Mishra, K. B.; Tiwari, V. K. Click Chemistry Inspired Synthesis of Morpholine-Fused Triazoles. J. Org. Chem. 2014, 79, 5752-5762. (g) Vekariya, R. H.; Liu, R.; Aubé, J. A Concomitant Allylic Azide Rearrangement/Intramolecular Azide– Alkyne Cycloaddition Sequence. Org. Lett. 2014, 16, 1844-1847. (h) Bera, S.; Panda, G. A Rapid Entry to Amino Acid Derived Diverse 3,4-Dihydropyrazines and Dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-Dipolar Cycloaddition. Org. Biomol. Chem. 2014, 12, 3976-3985. 15. For selected examples: (a) Ackermann, L.; Jayachandran, R.; Potukuchi, H. K.; Novak, P.; Buttner. L. Palladium-Catalyzed Dehydrogenative Direct Arylations of 1,2,3-Triazoles. Org. Lett. 2010, 10, 2056-2059. (b) Yan, J.; Zhou, F.; Qin, D.; Cai, T.; Ding, K.; Cai, Q. Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones through Copper-Catalyzed Tandem Reactions of N-(2-Haloaryl)propiolamides with Sodium



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Azide. Org. Lett. 2012, 14, 1262-1265. (c) Cai, Q.; Yan, J.; Ding, K. RutheniumCatalyzed Direct C–H Bond Arylations of Heteroarenes. Org. Lett. 2012, 14, 33323335. (d) Schulman, J. M.; Friedman, A. A.; Panteleev, J.; Lautens, M. Synthesis of 1,2,3-Triazole-Fused Heterocycles via Pd-Catalyzed Cyclization of 5-Iodotriazoles. Chem. Commun. 2012, 48, 55-57. (e) Brahma, K.; Achari, B.; Choudhury, C. Facile Synthesis

of

[1,2,3]-Triazole-Fused

Isoindolines,

Tetrahydroisoquinolines,

Benzoazepines and Benzoazocines by Palladium-Copper Catalysed Heterocyclisation. Synthesis 2013, 545-555. (f) Pericherla, K.; Jha, A.; Khungar, B.; Kumar, A. CopperCatalyzed Tandem Azide–Alkyne Cycloaddition, Ullmann Type C–N Coupling, and Intramolecular Direct Arylation. Org. Lett. 2013, 15, 4304-4307. (g) Sokolova, N. V.; Nenajdenko, V. G. Recent Advances in the Cu(I)-Catalyzed Azide–Alkyne Cycloaddition: Focus on Functionally Substituted Azides and Alkynes. RSC Adv. 2013, 3, 16212-16242. (h) For a recent review, see: Singh, M. S.; Choudhury, S.; Koley, S. Advances of Azide-Alkyne Cycloaddition-Click Chemistry over the Recent Decade. Tetrahedron 2016, 72, 5257-5283 and references cited therein. 16. For selected examples: (a) Oliva, A. I.; Christman, U.; Font, D.; Cuevas, F.; Ballester, P.; Buschmann, H.; Torrens, A.; Yenes, S.; Pericàs, M. A. Intramolecular Azide−Alkyne Cycloaddition for the Fast Assembly of Structurally Diverse, Tricyclic 1,2,3-Triazoles. Org. Lett. 2008, 10, 1617-1619. (b) Brawn, R. A.; Welzel, M.; Lowe, J. T.; Panek, J. S. Regioselective Intramolecular Dipolar Cycloaddition of Azides and Unsymmetrical Alkynes. Org. Lett. 2010, 12, 336-339. (c) Sau, M.; RodríguezEscrich, C.; Pericàs, M. A. Copper-Free Intramolecular Alkyne–Azide Cycloadditions Leading to Seven-Membered Heterocycles. Org. Lett. 2011, 13, 5044-5047. (d) Mani, N. S.; Fitzgerald, A. E. A Step-Economical Route to Fused 1,2,3-Triazoles via an Intramolecular 1,3-Dipolar Cycloaddition between a Nitrile and an in Situ Generated


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Aryldiazomethane. J. Org. Chem. 2014, 79, 8889-8894. (e) Ning, Y.; Wu, N.; Yu, H.; Liao, P.; Li, X.; Bi, X. Silver-Catalyzed Tandem Hydroazidation/Alkyne–Azide Cycloaddition of Diynes with TMS-N3: An Easy Access to 1,5-Fused 1,2,3-Triazole Frameworks. Org. Lett. 2015, 17, 2198-2201. (f) John, J.; Thomas, J.; Parekh, N.; Dehaen, W. Tandem Organocatalyzed Knoevenagel Condensation/1,3‐Dipolar Cycloaddition towards Highly Functionalized Fused 1,2,3‐Triazoles. Eur. J. Org. Chem. 2015, 4922-4930. (g) Xie, Y. -Y.; Wang, Y. -C.; He, Y.; Hu, D. -C.; Wang, H. S.; Pan, Y. -M. Catalyst-free Synthesis of Fused 1,2,3-Triazole and Isoindoline Derivatives via an Intramolecular Azide–alkene Cascade Reaction. Green Chem. 2017, 19, 656-659. 17. For selected recent examples, where p-QMs were used as 1,6-acceptors: (a) Zhang, X -Z.; Deng, Y. -H.; Gan, K. -J.; Yan, X.; Yu, K. -Y.; Wang, F. -X.; Fan, C. -A. Tandem Spirocyclopropanation/Rearrangement Reaction of Vinyl p-Quinone Methides with Sulfonium Salts: Synthesis of Spirocyclopentenyl p-Dienones. Org. Lett. 2017, 19, 1752-1755. (b) Yuan, Z.; Liu, L.; Pan, R.; Yao, H.; Lin, A. Silver-Catalyzed Cascade 1,6-Addition/Cyclization of para-Quinone Methides with Propargyl Malonates: An Approach to Spiro[4.5]deca-6,9-dien-8-ones. J. Org. Chem. 2017, 82, 8743-8751. (c) Xie, K. -X.; Zhang, Z. -P.; Li, X. Bismuth Triflate-Catalyzed Vinylogous Nucleophilic 1,6-Conjugate

Addition

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3-Propenyl-2-

silyloxyindoles. Org. Lett. 2017, 19, 6708-6711. (d) Mei, G. -J.; Xu, S. -L.; Zheng, W. -Q.; Bian, C. -Y.; Shi, F. [4 + 2] Cyclization of para-Quinone Methide Derivatives with Alkynes. J. Org. Chem. 2018, 83, 1414-1421. (e) Liu, T.; Liu, J.; Xia, S.; Meng, J.; Shen, X.; Zhu, X.; Chen, W.; Sun, C.; Cheng, F. Catalyst-Free 1,6-Conjugate Addition/Aromatization/Sulfonylation of para-Quinone Methides: Facile Access to Diarylmethyl Sulfones. ACS Omega 2018, 3, 1409-1415. (f) Zhao, K.; Zhi, Y.; Wang,



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A.; Enders, D. Synthesis of Malononitrile-Substituted Diarylmethines via 1,6Addition of Masked Acyl Cyanides to para-Quinone. Methides Synthesis 2018, 50, 872-880. (g) Liu, L.; Yuan, Z.; Pan, R.; Zeng, Y.; Lin, A.; Yao, H.; Huang, Y. 1,6Conjugate Addition-mediated [4 + 1] Annulation: An Approach to 2,3Dihydrobenzofurans. Org. Chem. Front. 2018, 5, 623-628. (h) Pan, R.; Hu, L.; Han, C.; Lin, A.; Yao, H. Cascade Radical 1,6-Addition/Cyclization of para-Quinone Methides: Leading to Spiro[4.5]deca-6,9-dien-8-ones. Org. Lett. 2018, 20, 1974-1977. 18. (a)

Reddy,

V.;

Anand,

Diarylindolylmethanes

R.

through

V.

Expedient

Access

Palladium-Catalyzed

to

Domino

Unsymmetrical Electrophilic

Cyclization–Extended Conjugate Addition Approach. Org. Lett. 2015, 17, 3390-3393. (b) Ramanjaneyulu, B. T.; Mahesh, S.; Anand, R. V. Bis(amino)cyclopropenylideneCatalyzed 1,6-Conjugate Addition of Aromatic Aldehydes to para-Quinone Methides: Expedient Access to α,α′-Diarylated Ketones. Org. Lett. 2015, 17, 3952-3955. (c) Arde, P.; Anand, R. V. N-Heterocyclic Carbene Catalysed 1,6-Hydrophosphonylation of p-Quinone Methides and Fuchsones: An Atom Economical Route to Unsymmetrical Diaryl- and Triarylmethyl Phosphonates. Org. Biomol. Chem. 2016, 14, 5550-5554. (d) Goswami, P.; Singh, G.; Anand, R. V. N-Heterocyclic Carbene Catalyzed 1,6-Conjugate Addition of Me3Si-CN to para-Quinone Methides and Fuchsones: Access to α-Arylated Nitriles. Org. Lett. 2017, 19, 1982-1985. (e) Jadhav, A. S.; Anand, R. V. 1,6-Conjugate Addition of Zinc Alkyls to para-Quinone Methides in a Continuous-flow Microreactor. Org. Biomol. Chem. 2017, 15, 56-60. (f) Jadhav, A. S.; Anand, R. V. TfOH Catalyzed 1,6-Conjugate Addition of Thiols to paraQuinone Methides Under Continuous-flow Conditions. Eur. J. Org. Chem. 2017, 3716-3721. (g) Singh, G.; Goswami, P.; Anand, R. V. Exploring Bis(amino)cyclopropenylidene as a Non-Covalent Brønsted Base Catalyst in Conjugate


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Addition Reactions. Org. Biomol. Chem. 2018, 16, 384-388. (h) Goswami, P.; Sharma, S.; Singh, G.; Anand, R. V. Bis(amino)cyclopropenylidene Catalyzed Rauhut-Currier Reaction Between α,β-Unsaturated Carbonyl Compounds and paraQuinone Methides. J. Org. Chem. 2018, 83, 4213-4220. 19. The reaction was purposefully performed using AgSbF6 as a catalyst at 45 oC as we found that the conversion of the 5a to the intermediate was fast and, at the same time, the conversion of the intermediate to the product 6a did not take place under this particular condition. 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 work-up. 21. Uno, T.; Yamamoto, S.; Yamane, A.; Kubo, M.; Itoh, T. Asymmetric Anionic Polymerizations

of

7‐(o‐Substituted-phenyl)‐2,6‐Dimethyl‐1,4‐Benzoquinone

Methides: Electrostatic Interaction and Steric, Inductive, and Resonance Effects of the ortho‐Substituent on the Optical Activity. Journal of Polymer Science Part A: Polymer Chemistry 2017, 55, 1048-1058.


Catalyzed 1,6-Conjugate Addition of Me3SiN3 to

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