A Facile One-Pot Synthesis of New Poly Functionalized Pyrrolotriazoles via a Regioselective Multicomponent Cyclisation and Suzuki–Miyaura Coupling Reactions

Abstract

The first access to N-1, N-4 disubstituted pyrrolo[2,3-d][1,2,3]triazoles is reported. The series were generated using a “one-pot” MCR, leading to a single regioisomer of the attempted heteroaromatic skeleton in good yields. Next, the functionalization of C-5 and C-6 positions was investigated. (Het)aryl groups were introduced at the C-5 and C-6 positions of the pyrrolo[2,3-d][1,2,3]triazoles using regioselective electrophilic brominations followed by Suzuki–Miyaura cross coupling reactions. Palladium-catalyzed cross-coupling conditions were optimized and a representative library of various boronic acids was employed to establish the scope and limitations of the method.

1. Introduction

Pyrrole and triazole derivatives are powerful moieties to elaborate drugs which are used in various areas of medicine as anticancer, antitubercular, and analgesic agents [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. For these reasons, their introduction in medicinal chemistry programs has grown, in particular in the context of molecular diversity and innovative chemical space research [18,19]. These two small heterocycles have been fused in bicyclic systems [20,21,22,23,24], providing original building blocks for medicinal chemists [25,26]. Nevertheless, the literature reports only one example of these two cycles combined together in a [5:5] fused ring which was designed by Cirrincione et al. to access benzylated pyrrolo[2,3-d][1,2,3]triazoles of type B [27]. To date no method is available to introduce the chosen substituents in N-1, N-4, C-5, and C-6 positions. This lack of references and methods induces a gap in the exploration of the chemical space and prompted us to search for novel and efficient strategies from a unique versatile platform towards highly diversified structures in a minimum number of steps.

The reported synthetic pathway leading to the targeted bicycle started from an appropriate polysubstituted pyrrole A to generate, after formation of the triazole moiety, the pyrrolo[2,3-d][1,2,3]triazole derivatives B (Figure 1). Despite the apparent efficiency of this step, molecular diversity cannot be easily managed under this method due to the limitations in terms of regioselective cyclisation and access or commercial availability of pyrrole derivatives.

In order to introduce a wide range of functional groups, a solution consists in building a library of pyrrolo[2,3-d][1,2,3]triazole platforms D from commercially available 3-pyrrholidinone C patterns and then elaborating its selective functionalization using arylation procedures. With this aim in view, our expertise in heterocyclic synthesis prompted us to envision the use of regioselective halogenation/Suzuki–Miyaura sequences from a versatile platform D that seems to be particularly powerful to tackle this challenge [28,29,30,31,32,33]. We report herein an unprecedented synthesis of tetra-substituted-pyrrolo[2,3-d][1,2,3]triazoles E, and the optimization of the experimental conditions. Lastly, the scope of both cross-coupling reactions on these two selected positions (Figure 1) is given.

2. Results and Discussion

First at all, we focused our attention on the access of pyrrolo[2,3-d][1,2,3]triazole 4, which can be prepared by using a single cascade step developed by Dehaen et al. from commercially available enolizable 3-pyrrolidinone 1 and p-methoxybenzylamine 2 in presence of 4-nitrophenylazide 3 and acetic acid as catalyst in air atmosphere (

Table 1. Optimization of conditions for the formation of 4.

Entry	PMBNH2 (eq.)	Azide 3 (eq.)	T (°C)	Time (h)	Solvent	4 c (%)
1	1.5	1.0	100 a	12	Toluene	30
2	1.5	1.0	140 a	12	Toluene	40
3	1.5	1.0	140 b	1	Toluene	41
4	1.5	1.0	140 b	1	THF	33
5	1.5	2.0	140 b	1	Toluene	48
6	3.0	2.0	140 b	1	Toluene	61
7	4.0	2.0	140 b	1	Toluene	56
8	3.0	3.0	140 b	1	Toluene	64
9	3.0	5.0	140 b	1	Toluene	75
10	3.0	6.0	140 b	1	Toluene	71

^a Classical thermal condition. ^b Microwave irradiation. ^c Yields are calculated after isolation of the product.

) [34]. The condensation of 3-pyrrolidinone with a primary amine under thermal conditions at 100 °C during 12 h generated the corresponding enamine, which, after a [3+2]cycloaddition reaction and aromatization with 4-nitroaniline as leaving group, gave only the regioisomer 4 in 30% of yield (the only degradation was observed with an inert atmosphere). The use of a sealed tube allowed us to reach a temperature of 140 °C and to slightly increase the yield of 4 to 40%. Under microwave activation, the reaction was achieved in only 1 h with a yield of 41%. To improve the efficiency of the reaction, the modulation of a few critical parameters was investigated. Replacing the solvent with THF induced a slight decrease in yield (33% versus 41% with toluene). Modulation of the numbers of equivalents of 2 and 3 was performed and the combination of 3.0 equivalents of 2 and 5.0 equivalents of azide derivative furnished 4 in a good yield of 75%. These conditions therefore appeared optimal for designing a representative library of compounds D.

The scope and potential limitations of the MCR step were then investigated by the modulation of the 3-pyrrolidinones and benzylamines (

Table 2. Scope of the MCR reaction: synthesis of 4–16 ^a,b.

4, 75%	5, 76%	6, 72%	7, 73%	8, 76%
9, 51%	10, 8%	11, 71%	12, 70%	13, Trace c
	14, 80%	15, 65%	16, 75%

^a General reaction conditions: 1.0 eq. of 3-pyrrolidinone derivative, 3.0 eq. of amine and 5.0 eq. of azide. ^b Yields are calculated after isolation of the products. ^c Detected by LCMS.

). First, whatever the modification of the nature of the substrates, the regioselectivity of the cyclization remained identical and only pyrrolo[2,3-d][1,2,3]triazole isomers were generated. The use of benzylamine or 4-methylbenzylamine was well tolerated and furnished the derivatives 5 and 6 in good yields. In contrast, the presence of electron-withdrawing substituents such as trifluoromethyl or nitro groups decreased the annelation efficiency, and compounds 9 and 10 were isolated in 51% and 8% yields, respectively.

Next, we investigated the influence of steric hindrance using a position switch of a methyl group on the phenyl ring. Whatever the position, the assay exhibited the same behaviour and each regioisomer was isolated with a 70% higher efficiency. Finally, the aromatic switch for heterocycles was studied with 2-(aminomethyl)-thiophene or -pyridine and once again, the efficiency of the reaction was preserved, and compounds 11 and 12 were isolated in 71% and 72% yields, respectively. The only identified limit concerned the use of aniline as amine source for compound 13, which totally inhibited the reaction due to its less nucleophile character compared to the benzyl amine derivative. Finally, the use of alkylamines restored the efficiency of the reaction, especially for the primary amine which exhibited a better reactivity than a secondary amine (14, 80% versus 15, 65%).

Selective halogenation in C-6 position with N-Bromosuccinimide in DCM at r.t. was performed on the complete library of derivatives of type D. The scope of the reaction was studied with a representative panel of previously synthesized pyrrolo[2,3-d][1,2,3]triazoles to afford derivatives 17–21 (

Table 3. C-6 bromination of pyrrolo[2,3-d][1,2,3]triazoles: synthesis of 17–21 ^a.

17, 93%	18, 87%	19, 90%	20, 70%	21, 90%

^a Yields are calculated after isolation of the product.

) with efficiency as bromo derivatives were mainly isolated in satisfying yields, except in the case of 15 for which the mono brominated compound 20 was obtained in a 70% yield but accompanied with a separable amount of dibrominated product as side product (20%).

With these compounds in hand, we then achieved the bromine displacement by Suzuki–Miyaura cross coupling to explore its reactivity, and also to access C-6 substituted pyrrolo[2,3-d][1,2,3]triazoles. This objective prompted us to find a general and efficient catalytic system by optimizing the main reaction parameters (

Table 4. Optimization of Suzuki–Miyaura cross-coupling.

Entry	Boronic Acid (eq.)	Catalyst (mol%)	Ligand (mol%)	Base (eq.)	22, Yield a (%)
1	1,2	Pd(PPh3)4 (3.0)	-	Na2CO3 (2.0)	19
2	1,2	Pd(PPh3)4 (3.0)	-	K2CO3 (2.0)	61
3	1,2	Pd(PPh3)4 (3.0)	-	Cs2CO3 (2.0)	61
4	1,2	Pd(PPh3)4 (3.0)	-	K3PO4 (2.0)	74
5	1,2	Pd(PPh3)4 (5.0)	-	K3PO4 (2.0)	74
6	1,2	Pd(OAc)2 (3.0)	XantPhos (6.0)	K3PO4 (2.0)	41
7	1,2	Pd(OAc)2 (3.0)	RuPhos (6.0)	K3PO4 (2.0)	80
8	1,5	Pd(OAc)2 (3.0)	RuPhos (6.0)	K3PO4 (2.0)	90

^a Yields are calculated after isolation of the product.

). First, we used 17 as starting material, Pd (PPh₃)₄ as the catalyst source, Na₂CO₃ as base, and 1,4-dioxane as a solvent under microwave irradiation for 1 h. With these conditions, the desired product 22 was isolated in a low but encouraging 19% yield (Table 4, entry 1). When the base was switched for K₂CO₃ or Cs₂CO₃, the reactivity was improved and the desired compound 22 was obtained in a 61% yield. The best result was reached with K₃PO₄ [35] with a good 74% yield for 22. Next, we investigated the influence of the catalyst system. We increased the catalytic load to 5% but no improvement was observed. In the following experiment, we tried to catalyze the reaction with a bidentate palladium complex, which was formed by using a mixture of Pd (OAc)₂ (3.0 mol%) and Xantphos (6.0 mol%). While this modification induced a dramatic decrease in yield, the reactivity was boosted with the well-known Buchwald-RuPhos ligand, and product 22 was isolated in a good yield of 80% (Table 4, entry 7). Finally, a fine adjustment of the quantities of boronic acid to 1.5 equivalents gave the optimized conditions with the best 90% yield.

Next, the scope and potential limitations of the Pd-coupling step were investigated by modulation of the boron derivatives (

Table 5. Scope of the Suzuki–Miyaura reaction in C-6 position: synthesis of 22–34 ^a.

22, 90%	23, 92%	24, 48%
25, 73%	26, 33%	27, 42% b
28, 57%	29, 60%	30, 29%
31, 91%	32, 83%	33, 82%
	34, 65%

^a Yields are calculated after isolation of the products. ^b LCMS estimated amount before purification.

). The use of simple phenyl boronic acid was well tolerated and furnished the derivative 23 in good yield. In contrast, the presence of electron-withdrawing or electron-donating substituents modulated the efficiency of the reaction.

In the last stage of this study, we investigated the reactivity of the C-5 position. Bromination was performed using the same conditions as those previously used for the C-6 position, and compounds 35–39 were isolated in excellent yields (

Table 6. C-5 bromination of pyrrolo[2,3-d][1,2,3]triazoles: synthesis of 35–39 ^a.

35, 86%	36, 80%	37, 90%	38, 90%	39, 95%

^a Yields are calculated after isolation of the products.

). The scope and generality of the Suzuki–Miyaura coupling step were then examined (

Table 7. Scope of the Suzuki–Miyaura reaction in C-5 position: synthesis of 40–53 ^a.

40, 75%	41, 97%	42, 88%	43, 76%
44, 83%	45, 88%	46, 48%	47, 49% (97% b from 48)
48, 96%	49, 55%	50, 96%	51, 70%
	52, 78%	53, 95%

^a Yields are calculated after the isolation of the products following purification. ^b Also obtained via deprotection of 48 in HCl 4 M in 1,4-dioxane, 20 h at r.t.

).

We used conditions involving K₃PO₄, Pd (OAc)₂ and RuPhos as the catalyst systems under microwave irradiation which have proved to be useful in the C-6 position. The arylation was successfully achieved with para-tolylboronic acid to afford 40 in a good 75% yield (Table 7). In the last stage of this study, we varied the nature of the boron derivative. In fact, whatever the substituent on the phenyl boronic acid (i.e., electron-donating or withdrawing), or the steric hindrance induced by an ortho substitution, the C-C bond was efficiently generated, and products were isolated in good to excellent yields (Table 7, products 40–53). The only identified limit concerned the use of the poorly soluble nitrophenylboronic and 4-hydroxyphenyl boronic acids, which slightly altered the yield of the corresponding reactions. This last constraint was easily circumvented by the use of an easily removable protective group such as THP, as 48 was obtained in a near-quantitative manner. The use of heteroarylboronic acid such as thiophene derivative was well tolerated, and compound 49 was isolated in a 55% yield. Finally, the influence of the substituents in N-1 or N-4 positions was investigated, and again no alteration was observed as compounds 50–53 were isolated in very good yields.

41 crystalizes in the monoclinic P2₁/c space group with one molecule in the asymmetric unit and consequently 4 molecules in the unit cell (Figure 2, see Table 1 in ESI for crystallographic data). The molecular volume is high (443 ų) as the benzyl and phenyl moieties are not coplanar with the central pyrrolo–triazole ring. The two phenyls on position 5 and 6 are respectively tilted from 38.76 (4)° and 71.48 (6)° from the mean plane of the central pyrrolo–triazole ring, and benzyl groups on position 1 and 4 are almost perpendicular to the pyrrolo–triazole mean plane (86.06 (4)° and 83.60 (5)°, respectively). The phenyl ring holding a methyl in the meta position is disordered onto two positions corresponding to a rotation of 180° around the C–C bond linked to central double ring. The methyl moieties are then distributed either above (60%) or below (40%) the central ring. The cohesion of the network is essentially ensured by weak Van Der Waals interactions without any π-π staking despite the numerous aromatic rings as supported by Hirshfeld surface analysis (Figure 3).

3. Conclusions

In summary, the quick access to original N-1, N-4 disubstituted pyrrolo[2,3-d][1,2,3]triazoles has been described herein using a one-pot MCR leading to a single regioisomer of the attempted heteroaromatic skeleton in good yields. The functionalization of C-5 and C-6 positions was also investigated. First, a regioselective halogenation was performed in the C-6 position followed by Suzuki–Miyaura coupling reaction to introduce (Het)aryl moiety with success. Next, the same sequence was also realized with the last free C-5 functionalizable position, with the same efficiency. The scope of the Suzuki–Miyaura reactions for each position was studied and showed an excellent compatibility with a wide range of boronic acids. This work allows access to a novel class of tetra substituted pyrrolo[2,3-d][1,2,3]triazoles which will undoubtedly have a major impact on the further synthesis of new bioactive compounds that contain the rare pyrrolo[2,3-d][1,2,3]triazole scaffold as the central skeleton. Efforts to achieve these objectives, and particularly to study the reactivity of the triazolic nitrogen atoms involved in the bicyclic system, are currently in progress.

4. Materials and Methods

4.1. General Information

¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl₃ and DMSO-d₆. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet), and dd (doublet of doublets). All compounds were characterized by ¹H NMR, and ¹³C NMR which are consistent with those reported in the literature (Supplementary Materials). Melting points are uncorrected. IR absorption spectra were obtained on a PerkinElmer PARAGON 1000 PC, and the values are reported in inverse centimeters. HRMS spectra were acquired in positive mode with an ESI source on a Q-TOF mass by the “Fédération de Recherche” ICOA/CBM (FR2708) platform and NMR data were generated on the Salsa platform. Monitoring of the reactions was performed using silica gel TLC plates (silica Merck 60 F 254). Spots were visualized by UV light (254 nm and 356 nm). Column chromatography was performed using silica gel 60 (0.063–0.200 mm, Merck). Microwave irradiation was carried out in sealed vessels placed in a Biotage Initiator or Biotage Initiator+ system (400 W maximum power). The temperatures were measured externally by IR. Pressure was measured by a non-invasive sensor integrated into the cavity lid. All reagents were purchased from commercial suppliers and were used without further purification.

4.2. General Procedure (A) for 4–16

In a microwave vial already filled with anhydrous Toluene (0.25 M) and molecular sieves (3 Å), were successively added pyrrolidinone (1.0 eq.), amine (3.0 eq.), 1-Azido-4-nitrobenzene (5.0 eq.), and acetic acid (0.3 eq.). The vial was finally capped and stirred 1 h at 140 °C under microwave irradiation. The resulting mixture was reduced in a vacuum and filtered on charcoal. The crude product was purified by flash silica gel column chromatography using DCM, then PE/EtOAc mixtures to obtain the desired compound.

4.2.1. 4-Benzyl-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (4)

The reaction was carried out as described in general procedure A using 4-methoxybenzylamine (206 mg, 1.5 mmol, 3.0 eq.), 1-benzyl-3-pyrrolidinone (88.0 mg, 0.5 mmol, 1.0 eq.), 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9.0 mg, 0.15 mmol, 0.3 eq.), and 50 mg of molecular sieves (3 Å) in anhydrous Toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 4 as a white solid (119.0 mg, 75%). R_f = 0.27 (PE/EtOAc: 70/30). Mp 89–91 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.32–7.26 (m, 7H), 6.88 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 3.1 Hz, 1H), 5.55 (d, J = 3.1 Hz, 1H), 5.52 (s, 2H), 5.23 (s, 2H), 3.80 (s, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 159.8 (C_q), 150.9 (C_q), 137.0 (C_q), 130.3 (CH_Ar), 130.1 (2 × CH_Ar), 128.9 (2 × CH_Ar), 128.1 (CH_Ar), 127.9 (C_q), 127.9 (2 × CH_Ar), 127.0 (C_q), 114.3 (2 × CH_Ar), 88.6 (CH_Ar), 55.4 (CH₃), 53.3 (CH₂), 50.6 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3101, 3038, 2928, 2836, 1611, 1431, 1302, 1184, 1084, 751, 637. HRMS (EI⁺) m/z calcd for C₁₈H₁₉N₄O [M+H]⁺: 319.1553, found: 319.1555.

4.2.2. 1,4-Dibenzyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (5)

The reaction was carried out as described in general procedure A using benzylamine (161 mg, 1.5 mmol, 3.0 eq.), 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.), 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 5 as a yellow solid (110 mg, 76%). R_f = 0.25 (PE/EtOAc: 80/20). Mp 107–109 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.38–7.22 (m, 10H), 6.79 (d, J = 3.2 Hz, 1H), 5.59 (s, 2H), 5.57 (d, J = 3.2 Hz, 1H), 5.24 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.9 (C_q), 137.0 (C_q), 134.9 (C_q), 130.4 (CH_Ar), 129.0 (2 × CH_Ar), 128.9 (2 × CH_Ar), 128.5 (CH_Ar), 128.5 (2 × CH_Ar), 128.1 (CH_Ar), 128.0 (C_q), 127.8 (2 × CH_Ar), 88.5 (CH_Ar), 53.7 (CH₂), 50.6 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3085, 3032, 2971, 1520, 1313, 1169, 1075, 938, 727, 694. HRMS (EI⁺) m/z calcd for C₁₈H₁₇N₄ [M+H]⁺: 289.1448, found: 289.1450.

4.2.3. 4-Benzyl-1-(4-methylbenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (6)

The reaction was carried out as described in general procedure A using 4-methylbenzylamine (182 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 6 as a white solid (103 mg, 72%). R_f = 0.21 (PE/EtOAc: 80/20). Mp 70–72 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.32–7.20 (m, 7H), 7.15 (m, 2H), 6.78 (d, J = 3.2 Hz, 1H), 5.57 (d, J = 3.2 Hz, 1H), 5.53 (s, 2H), 5.22 (s, 2H), 2.32 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.8 (C_q), 138.3 (C_q), 137.0 (C_q), 131.9 (C_q), 130.3 (CH_Ar), 129.6 (2 × CH_Ar), 128.9 (2 × CH_Ar), 128.5 (2 × CH_Ar), 128.0 (CH_Ar), 127.9 (C_q), 127.8 (2 × CH_Ar), 88.5 (CH_Ar), 53.5 (CH₂), 50.6 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3098, 3030, 2934, 2838, 1612, 1494, 1351, 1111, 1082, 972, 818, 773. HRMS (EI⁺) m/z calcd for C₁₉H₁₉N₄ [M+H]⁺: 303.1604, found: 303.1608.

4.2.4. 4-Benzyl-1-(3-methylbenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (7)

The reaction was carried out as described in general procedure A using 3-methylbenzylamine (182 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 7 as a white solid (105 mg, 73%). R_f = 0.21 (PE/EtOAc: 80/20). Mp 58–60 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.32–7.21 (m, 6H), 7.13 (m, 3H), 6.79 (d, J = 3.2 Hz, 1H), 5.59 (d, J = 3.2 Hz, 1H), 5.55 (s, 2H), 5.24 (s, 2H), 2.33 (s, 3H, H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.9 (C_q), 138.7 (C_q), 137.0 (C_q), 134.8 (C_q), 130.4 (CH_Ar), 129.3 (CH_Ar), 129.2 (CH_Ar), 128.9 (2 × CH_Ar), 128.8 (CH_Ar), 128.1 (CH_Ar), 128.0 (C_q), 127.8 (2 × CH_Ar), 125.6 (CH_Ar), 88.5 (CH_Ar), 53.7 (CH₂), 50.6 (CH₂), 21.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3028, 2927, 1518, 1366, 1201, 1099, 938, 770, 691. HRMS (EI⁺) m/z calcd for C₁₉H₁₉N₄ [M+H]⁺: 303.1604, found: 303.1609.

4.2.5. 4-Benzyl-1-(2-methylbenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (8)

The reaction was carried out as described in general procedure A using 4-methylbenzylamine (182 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 8 as a white solid (107 mg, 76%). R_f = 0.21 (PE/EtOAc: 80/20). Mp 73–75 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.36–7.19 (m, 9H), 6.75 (d, J = 3.2 Hz, 1H), 5.60 (s, 2H), 5.35 (d, J = 3.2 Hz, 1H), 5.23 (s, 2H), 2.38 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.7 (C_q), 137.5 (C_q), 137.0 (C_q), 132.7 (C_q), 130.9 (CH_Ar), 130.3 (CH_Ar), 129.9 (CH_Ar), 129.0 (CH_Ar), 128.9 (2 × CH_Ar), 128.0 (CH_Ar), 128.0 (C_q), 127.8 (2 × CH_Ar), 126.4 (CH_Ar), 88.5 (CH_Ar), 52.0 (CH₂), 50.6 (CH₂), 19.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3029, 2922, 1519, 1453, 1343, 1175, 1074, 924, 734, 696. HRMS (EI⁺) m/z calcd for C₁₉H₁₉N₄ [M+H]⁺: 303.1604, found: 303.1605.

4.2.6. 4-Benzyl-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (9)

The reaction was carried out as described in general procedure A using 4-(trifluoromethyl)benzylamine (263 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 9 as a beige solid (91 mg, 51%). R_f = 0.13 (PE/EtOAc: 80/20). Mp 105–107 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.61 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.37–7.24 (m, 5H), 6.85 (d, J = 3.2 Hz, 1H), 5.68–5.63 (m, 3H), 5.26 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.9 (C_q), 139.1 (C_q), 136.8 (C_q), 131.32–130.24 (m, C_q and CH_Ar), 129.0 (2 × CH_Ar), 128.5 (2 × CH_Ar), 128.2 (CH_Ar), 127.9 (C_q), 127.9 (2 × CH_Ar), 126.00 (q, J = 3.7 Hz, 2 × CH_Ar), 124.03 (d, J = 272.2 Hz, C_q), 88.1 (CH_Ar), 53.0 (CH₂), 50.7 (CH₂). ¹⁹F NMR (376 MHz, Chloroform-d): δ −62.7. IR (ATR diamond, cm⁻¹) ν: 2169, 1990, 1521, 1327, 1157, 1066, 1018, 819, 744, 715. HRMS (EI⁺) m/z calcd for C₁₉H₁₆F₃N₄ [M+H]⁺: 357.1322, found: 357.1323.

4.2.7. 4-Benzyl-1-(4-nitrobenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (10)

The reaction was carried out as described in general procedure A using 4-nitrobenzylamine hydrochloride (283 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 10 as a white solid (13 mg, 8%). R_f = 0.13 (PE/EtOAc: 80/20). Mp 123–125 °C. ¹H NMR (400 MHz, Chloroform-d): δ 8.21 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.35–7.28 (m, 5H), 6.88 (d, J = 3.2 Hz, 1H), 5.74–5.67 (m, 3H), 5.27 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.9 (C_q), 148.1 (C_q), 142.3 (C_q), 136.7 (C_q), 131.1 (CH_Ar), 130.1 (C_q), 129.0 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.2 (CH_Ar), 127.9 (2 × CH_Ar), 124.3 (2 × CH_Ar), 87.9 (CH_Ar), 52.7 (CH₂), 50.8 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3062, 2937, 2850, 1518, 1341, 1241, 1105, 932, 873, 783, 696, 619. HRMS (EI⁺) m/z calcd for C₁₉H₁₆N₅O₂ [M+H]⁺: 334.1299, found: 334.1297.

4.2.8. 4-Benzyl-1-(thiophen-2-ylmethyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (11)

The reaction was carried out as described in general procedure A using 2-thiophènemethylbenzylamine (170 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 11 as a brown solid (105 mg, 71%). R_f = 0.22 (PE/EtOAc: 80/20). Mp 65–67 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.31 (m, 6H), 7.16 (m, 1H), 7.02 (m, 1H), 6.85 (d, J = 3.2 Hz, 1H), 5.80 (s, 2H), 5.71 (d, J = 3.2 Hz, 1H), 5.27 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.8 (C_q), 136.9 (C_q), 136.7 (C_q), 130.5 (CH_Ar), 128.9 (2 × CH_Ar), 128.2 (CH_Ar), 128.1 (CH_Ar), 127.8 (2 × CH_Ar), 127.7 (C_q), 127.2 (CH_Ar), 126.7 (CH_Ar), 88.5 (CH_Ar), 50.6 (CH₂), 48.0 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3101, 2918, 1600, 1520, 1360, 1273, 1172, 1029, 853, 751, 694. HRMS (EI+) m/z calcd for C₁₆H₁₅N₄S [M+H]⁺: 295.1012, found: 295.1013.

4.2.9. 4-Benzyl-1-(pyridin-2-ylmethyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (12)

The reaction was carried out as described in general procedure A using pyridin-2-ylmethanamine (162 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-Azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 12 as a yellow solid (101 mg, 70%). R_f = 0.22 (PE/EtOAc: 50/50). Mp 79–81 °C. ¹H NMR (400 MHz, Chloroform-d): δ 8.59 (dd, J = 5.0, 1.8 Hz, 1H), 7.61 (td, J = 7.7, 1.8 Hz, 1H), 7.34–7.25 (m, 5H), 7.21 (dd, J = 7.7, 5.0 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 3.2 Hz, 1H), 5.80 (d, J = 3.2 Hz, 1H), 5.74 (s, 2H), 5.25 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 155.2 (C_q), 150.8 (C_q), 149.5 (CH_Ar), 137.2 (CH_Ar), 136.8 (C_q), 130.6 (CH_Ar), 128.8 (2 × CH_Ar), 128.3 (C_q), 128.0 (CH_Ar), 127.8 (2 × CH_Ar), 123.1 (CH_Ar), 122.2 (CH_Ar), 88.5 (CH_Ar), 55.1 (CH₂), 50.6 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3091, 3032, 2956, 2933, 2359, 1612, 1514, 1300, 1171, 1027, 832, 759. HRMS (EI⁺) m/z calcd for C₁₇H₁₆N₅ [M+H]⁺: 290.1400, found: 290.1405.

4.2.10. 4-Benzyl-1-propyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (14)

The reaction was carried out as described in general procedure A using propylamine (89 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 14 as an orange oil (96 mg, 80%). R_f = 0.15 (PE/EtOAc: 80/20). ¹H NMR (400 MHz, Chloroform-d): δ 7.39–7.21 (m, 5H), 6.88 (d, J = 3.2 Hz, 1H), 5.96 (d, J = 3.2 Hz, 1H), 5.26 (s, 2H), 4.39 (t, J = 7.4 Hz, 2H), 1.99 (h, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.8 (C_q), 137.1 (C_q), 130.3 (CH_Ar), 128.9 (2 × CH_Ar), 128.0 (C_q and CH_Ar), 127.8 (2 × CH_Ar), 88.1 (CH_Ar), 51.4 (CH₂), 50.6 (CH₂), 23.0 (CH₂), 11.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3031, 2956, 2933, 2875, 1733, 1519, 1355, 1268, 1144, 1026, 900, 731, 696. HRMS (EI⁺) m/z calcd for C₁₄H₁₇N₄ [M+H]⁺: 241.1448, found: 241.1448.

4.2.11. 4-Benzyl-1-isopropyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (15)

The reaction was carried out as described in general procedure A using isopropylamine (89 mg, 1.5 mmol, 3.0 eq.) as amine, 1-benzyl-3-pyrrolidinone (88 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 15 as a brown oil (78 mg, 65%). R_f = 0.26 (PE/EtOAc: 80/20). ¹H NMR (400 MHz, Chloroform-d): δ 7.40–7.25 (m, 5H), 6.90 (d, J = 3.2 Hz, 1H), 6.00 (d, J = 3.2 Hz, 1H), 5.27 (s, 2H), 4.95 (hept, J = 6.8 Hz, 1H), 1.64 (d, J = 6.8 Hz, 6H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.8 (C_q), 137.0 (C_q), 129.9 (CH_Ar), 128.8 (2 × CH_Ar), 128.0 (CH_Ar), 127.8 (2 × CH_Ar), 126.2 (C_q), 88.7 (CH_Ar), 52.5 (CH), 50.5 (CH₂), 22.3 (2 × CH₃). IR (ATR diamond, cm⁻¹) ν: 3030, 2977, 2931, 1518, 1488, 1388, 1242, 1077, 1028, 727, 697. HRMS (EI+) m/z calcd for C₁₄H₁₇N₄ [M+H]⁺: 241.1448, found: 241.1452.

4.2.12. 1-(4-Methoxybenzyl)-4-methyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (16)

The reaction was carried out as described in general procedure A using 4-methoxybenzylamine (206 mg, 1.5 mmol, 3.0 eq.) as amine, 1-methyl-3-pyrrolidinone (50 mg, 0.5 mmol, 1.0 eq.) as pyrrolidinone, 1-Azido-4-nitrobenzene (410.2 mg, 2.5 mmol, 5.0 eq.), acetic acid (9 mg, 0.15 mmol, 0.3 eq.), and 50 mg molecular sieves (3 Å) in anhydrous toluene (0.25 M). The crude mixture was purified by flash chromatography on silica gel using first DCM and then (PE/EtOAc: 80/20) to afford 16 as a yellow oil (58 mg, 48%). R_f = 0.17 (PE/EtOAc: 70/30). ¹H NMR (400 MHz, Chloroform-d): δ 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 3.1 Hz, 1H), 5.54 (d, J = 3.1 Hz, 1H), 5.52 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.7 (C_q), 151.0 (C_q), 131.3 (CH_Ar), 129.8 (2 × CH_Ar), 127.6 (C_q), 127.0 (C_q), 114.2 (2 × CH_Ar), 87.7 (CH_Ar), 55.3 (CH₃), 53.1 (CH₂), 33.0 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2162, 2002, 1612, 1512, 1303, 1222, 1174, 1028, 819, 740, 702. HRMS (EI+) m/z calcd for C₁₃H₁₅N₄O [M+H]⁺: 243.1240, found: 243.1245.

4.3. General Procedure (B) for the Bromination of C-6 Position of 1,4-dihydropyrrolo[2,3-d][1,2,3]triazole Derivatives 17–21

To a solution of corresponding 1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative (1.0 eq.) in DCM (0.05 M) was added N-bromosuccinimide (1.0 eq.) and the mixture was stirred 1 h at room temperature. The resulting mixture was quenched using water and phases were separated. The aqueous phase was extracted with DCM and combined organic phases were washed with brine and dried over MgSO₄. After being concentrated under vacuum conditions, the residue was purified by flash chromatography on silica gel affording the desired 6-bromo-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative.

4.3.1. 4-Benzyl-6-bromo-1-(4-Methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (17)

The reaction was carried out as described in general procedure B using 4-benzyl-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 4 (67 mg, 0.21 mmol, 1.0 eq.), and NBS (39 mg, 0.21 mmol, 1.0 eq.) in DCM (0.05 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 17 as a beige solid (78 mg, 93%). R_f = 0.55 (PE/EtOAc: 70/30). Mp 88–90 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.38–7.27 (m, 7H), 6.85 (d, J = 8.7 Hz, 2H), 6.82 (s, 1H), 5.57 (s, 2H), 5.20 (s, 2H), 3.78 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.8 (C_q), 150.3 (C_q), 136.2 (C_q), 129.7 (2 × CH_Ar), 129.4 (CH_Ar), 129.1 (2 × CH_Ar), 128.4 (CH_Ar), 128.1 (2 × CH_Ar), 127.8 (C_q), 126.1 (C_q), 114.3 (2 × CH_Ar), 74.7 (C_q), 55.4 (O-CH₃), 52.5 (CH₂), 51.0 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3098, 2934, 2858, 1612, 1463, 1280, 1027, 928, 759, 636. HRMS (EI+) m/z calcd for C₁₉H₁₈BrN₄O [M+H]⁺: 397.0659, found: 397.0655.

4.3.2. 4-Benzyl-6-bromo-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (18)

The reaction was carried out as described in general procedure B using 4-benzyl-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 9 (241 mg, 0.68 mmol, 1.0 eq.), and NBS (130 mg, 0.68 mmol, 1.0 eq.) in DCM (0.05 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 18 as a yellow solid (257 mg, 87%). R_f = 0.70 (PE/EtOAc: 70/30). Mp 93–95 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.60 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.41–7.28 (m, 5H), 6.86 (s, 1H), 5.69 (s, 2H), 5.22 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.2 (C_q), 139.5 (C_q), 136.0 (C_q), 130.8 (d, J = 32.5 Hz, C_q), 129.7 (CH_Ar), 129. (2 × CH_Ar), 128.5 (CH_Ar), 128.4 (2 × CH_Ar), 128.1 (2 × CH_Ar), 126.2 (C_q), 126.0 (q, J = 3.8 Hz, 2 × CH_Ar), 124.0 (d, J = 272.2 Hz, C_q), 74.5 (C_q), 52.3 (CH₂), 51.0 (CH₂). ¹⁹F NMR (376 MHz, Chloroform-d): δ −62.7. IR (ATR diamond, cm⁻¹) ν: 1323, 1155, 1111, 1066, 789, 776, 726, 698. HRMS (EI+) m/z calcd for C₁₉H₁₅BrF₃N₄ [M+H]⁺: 435.0427, found: 435.0423.

4.3.3. 4-Benzyl-6-bromo-1-(thiophen-2-ylmethyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (19)

The reaction was carried out as described in general procedure B using 4-benzyl-1-(thiophen-2-ylmethyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 11 (62 mg, 0.21 mmol, 1.0 eq.), and NBS (39 mg, 0.21 mmol, 1.0 eq.) in DCM (0.05 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 19 as a yellow pale solid (68 mg, 90%). R_f = 0.27 (PE/EtOAc: 80/20). Mp: 96–96 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.38–7.22 (m, 6H), 7.20–7.13 (m, 1H), 6.98–6.93 (m, 1H), 6.84 (s, 1H), 5.81 (s, 2H), 5.20 (s, 2H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.1 (C_q), 137.6 (C_q), 136.2 (C_q), 129.6 (CH_Ar), 129.1 (2 × CH_Ar), 128.5 (CH_Ar), 128.1 (2 × CH_Ar), 127.9 (CH_Ar), 127.2 (CH_Ar), 126.7 (CH_Ar), 126.0 (C_q), 74.8 (C_q), 51.0 (CH₂), 47.5 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3107, 2164, 2015, 1516, 1334, 1180, 1070, 929, 748, 669. HRMS (EI+) m/z calcd for C₁₆H₁₄BrN₄S [M+H]⁺: 373.0117, found: 373.0114.

4.3.4. 4-Benzyl-6-bromo-1-isopropyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (20)

The reaction was carried out as described in general procedure B using 4-benzyl-1-isopropyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 15 (50 mg, 0.21 mmol, 1.0 eq.), and NBS (39 mg, 0.21 mmol, 1.0 eq.) in DCM (0.05 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 20 as an orange oil (48 mg, 70%). R_f = 0.38 (PE/EtOAc: 80/20). ¹H NMR (400 MHz, Chloroform-d): δ 7.35–7.25 (m, 5H), 6.87 (s, 1H), 5.20 (s, 2H), 5.04 (hept, J = 6.8 Hz, 1H), 1.67 (d, J = 6.8 Hz, 6H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.3 (C_q), 136.2 (C_q), 129.0 (CH_Ar), 128.9 (2 × CH_Ar), 128.0 (CH_Ar), 127.9 (2 × CH_Ar), 124.9 (C_q), 74.6 (C_q), 52.9 (CH), 50.7 (CH₂), 22.8 (2 × CH₃). IR (ATR diamond, cm⁻¹) ν: 2978, 1512, 1454, 1344, 1178, 1145, 1126, 1062, 923, 729. HRMS (EI+) m/z calcd for C₁₄H₁₆BrN₄ [M+H]⁺: 319.0553, found: 319.0554.

4.3.5. 6-bromo-1-(4-methoxybenzyl)-4-methyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (21)

The reaction was carried out as described in general procedure B using 1-(4-methoxybenzyl)-4-methyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 16 (51 mg, 0.21 mmol, 1.0 eq.), and NBS (39 mg, 0.21 mmol, 1.0 eq.) in DCM (0.05 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 21 as a white solid (61 mg, 90%). R_f = 0.30 (PE/EtOAc: 70/30). Mp 123–125 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.33 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.82 (s, 1H), 5.57 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.7 (C_q), 150.5 (C_q), 130.5 (CH_Ar), 129.6 (2 × CH_Ar), 127.9 (C_q), 126.0 (C_q), 114.3 (2 × CH_Ar), 73.8 (C_q), 55.4 (CH₃), 52.5 (CH₂), 33.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2980, 2160, 1610, 1514, 1300, 1251, 1078, 1028, 948, 819, 750. HRMS (EI+) m/z calcd for C₁₃H₁₄BrN₄O [M+H]⁺: 321.0346, found: 321.0340.

4.4. General Procedure (C): Suzuki–Miyaura Cross-Coupling in C-6 Position of 6-bromo-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole Derivative 22–33

A solution of corresponding 6-bromo-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative (1.0 eq.), potassium phosphate tribasic (2.0 eq.), and corresponding aryl boronic acid (1.5 eq.) in dry 1,4-dioxane (0.15 M) was degassed by argon bubbling for 15 min. Pd (OAc)₂ (0.03 eq.) and RuPhos (0.06 eq.) were added and the mixture was heated at 120 °C for 1 h under microwave irradiation. The reaction mixture was filtered through a pad of celite, and the filtrate was reduced to dryness under vacuum. The residue was taken up in DCM, washed with water and dried over MgSO₄. After being concentrated under vacuum conditions, the residue was purified by flash chromatography on silica gel affording the desired 6-Arylated 1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative.

4.4.1. 4-Benzyl-1-(4-methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (22)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (70 mg, 0.18 mmol, 1.0 eq.), p-tolyl boronic acid (37 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 22 as a white solid (66 mg, 90%). R_f = 0.25 (PE/EtOAc: 70/30). Mp 91–93 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.37 (m, 4H), 7.34–7.29 (m, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 6.75 (d, J = 8.7 Hz, 2H), 5.67 (s, 2H), 5.31 (s, 2H), 3.76 (s, 3H), 2.38 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 151.4 (C_q), 136.8 (C_q), 136.2 (C_q), 130.4 (C_q), 129.5 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.2 (C_q), 128.2 (CH_Ar), 128.0 (2 × CH_Ar), 127.4 (2 × CH_Ar), 127.4 (CH_Ar), 125.8 (C_q), 114.1 (2 × CH_Ar), 107.2 (C_q), 55.4 (CH₃), 53.1 (CH₂), 50.7 (CH₂), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2930, 2835, 1611, 1535, 1245, 1174, 1071, 945, 733, 597. HRMS (EI+) m/z calcd for C₂₆H₂₅N₄O [M+H]⁺: 409.2023, found: 409.2021.

4.4.2. 4-Benzyl-1-(4-methoxybenzyl)-6-phenyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (23)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (70 mg, 0.18 mmol, 1.0 eq.), phenyl boronic acid (33 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd(OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 23 as a white solid (65 mg, 92%). R_f = 0.47 (PE/EtOAc: 70/30). Mp 127–129 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.36–7.20 (m, 10H), 7.01 (d, J = 8.3 Hz, 2H), 6.96 (s, 1H), 6.74 (d, J = 8.3 Hz, 2H), 5.65 (s, 2H), 5.29 (s, 2H), 3.73 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 151.5 (C_q), 136.7 (C_q), 133.4 (C_q), 129.0 (2 × CH_Ar), 128.9 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.2 (CH_Ar), 128.2 (C_q), 128.1 (2 × CH_Ar), 127.5 (3 × CH_Ar), 126.6 (CH_Ar), 125.7 (C_q), 114.2 (2 × CH_Ar), 107.3 (C_q), 55.4 (CH₃), 53.1 (CH₂), 50.7 (CH₂). IR (ATR diamond, cm⁻¹) ν: 2162, 2009, 1512, 1348, 1300, 1251, 1026, 908, 792, 669, 582. HRMS (EI+) m/z calcd for C₂₅H₂₃N₄O [M+H]⁺: 395.1866, found: 395.1865.

4.4.3. 4-Benzyl-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (24)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (70 mg, 0.18 mmol, 1.0 eq.), p-methoxyphenyl boronic acid (41 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 24 as a beige solid (37 mg, 48%). R_f = 0.37 (PE/EtOAc: 70/30). Mp 87–89 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.38–7.27 (m, 5H), 7.20 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.89 (s, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.62 (s, 2H), 5.28 (s, 2H), 3.82 (s, 3H), 3.74 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 158.6 (C_q), 151.4 (C_q), 136.9 (C_q), 129.0 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.2 (C_q), 128.1 (CH_Ar), 128.0 (2 × CH_Ar), 127.1 (CH_Ar), 125.9 (C_q), 125.8 (C_q), 114.3 (2 × CH_Ar), 114.1 (2 × CH_Ar), 106.8 (C_q), 55.5 (CH₃), 55.3 (CH₃), 53.0 (CH₂), 50.6 (CH₂). IR (ATR diamond, cm⁻¹) ν: 2924, 2167, 2029, 1514, 1300, 1176, 1028, 948, 835, 785, 736, 675, 592. HRMS (EI+) m/z calcd for C₂₆H₂₅N₄O₂ [M+H]⁺: 425.1972, found: 425.1967.

4.4.4. 4-Benzyl-1-(4-methoxybenzyl)-6-(m-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (25)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-Methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 22 (70 mg, 0.18 mmol, 1.0 eq.), m-tolyl boronic acid (37 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 25 as a yellow oil (54 mg, 73%). R_f = 0.25 (PE/EtOAc: 70/30). ¹H NMR (400 MHz, Chloroform-d): δ 7.37–7.27 (m, 5H), 7.24–7.18 (m, 1H), 7.13–7.08 (m, 2H), 7.07–7.01 (m, 3H), 6.97 (s, 1H), 6.79–6.74 (d, J = 8.7 Hz, 2H), 5.66 (s, 2H), 5.30 (s, 2H), 3.74 (s, 3H), 2.31 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 151.5 (C_q), 138.4 (C_q), 136.8 (C_q), 133.2 (C_q), 129.0 (2 × CH_Ar), 128.7 (CH_Ar), 128.7 (2 × CH_Ar), 128.2 (C_q), 128.2 (CH_Ar), 128.1 (CH_Ar), 128.0 (2 × CH_Ar), 127.5 (CH_Ar), 127.3 (CH_Ar), 125.7 (C_q), 124.5 (CH_Ar), 114.2 (2 × CH_Ar), 107.4 (C_q), 55.4 (CH₃), 53.1 (CH₂), 50.7 (CH₂), 21.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3034, 2920, 1608,1531, 1506, 1350, 1246, 1029, 914, 779. HRMS (EI+) m/z calcd for C₂₆H₂₅N₄O [M+H]⁺: 409.2023, found: 409.2020.

4.4.5. 4-Benzyl-1-(4-methoxybenzyl)-6-(o-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (26)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-Methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (70 mg, 0.18 mmol, 1.0 eq.), o-tolyl boronic acid (37 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 26 as a yellow oil (24 mg, 33%). R_f = 0.25 (PE/EtOAc: 70/30). ¹H NMR (400 MHz, Chloroform-d): δ 7.35–7.28 (m, 5H), 7.25–7.20 (m, 2H), 7.18–7.12 (m, 1H), 7.10–7.06 (m, 1H), 6.77 (d, J = 8.7 Hz, 2H), 6.75 (s, 1H), 6.61 (d, J = 8.7 Hz, 2H), 5.36 (s, 2H), 5.28 (s, 2H), 3.72 (s, 3H), 2.10 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 149.0 (C_q), 137.1 (C_q), 137.0 (C_q), 132.6 (C_q), 131.1 (CH_Ar), 130.2 (CH_Ar), 129.4 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.6 (CH_Ar), 128.1 (CH_Ar), 127.9 (2 × CH_Ar), 127.8 (C_q), 127.6 (CH_Ar), 126.9 (C_q), 125.7 (CH_Ar), 113.9 (2 × CH_Ar), 105.0 (C_q), 55.4 (CH₃), 52.9 (CH₂), 50.7 (CH₂), 20.6 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2924, 1610, 1454, 1348, 1246, 1157, 1029, 796, 768. HRMS (EI+) m/z calcd for C₂₆H₂₅N₄O [M+H]⁺: 409.2023, found: 409.2019.

4.4.6. 4-Benzyl-1-(4-methoxybenzyl)-6-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (28)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (70 mg, 0.18 mmol, 1.0 eq.), 4-(trifluoromethyl)phenyl boronic acid (51 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 28 as a yellow solid (47 mg, 57%). R_f = 0.42 (PE/EtOAc: 70/30). Mp 111–113 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.53 (d, J = 8.1 Hz, 2H), 7.40–7.29 (m, 7H), 7.04 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 5.67 (s, 2H), 5.31 (s, 2H), 3.73 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.5 (C_q), 151.7 (C_q), 137.1 (C_q), 136.4 (C_q), 129.1 (2 × CH_Ar), 128.5 (2 × CH_Ar), 128.4 (CH_Ar), 128.2 (C_q), 128.1 (2 × CH_Ar), 128.0 (CH_Ar), 127.8 (C_q), 127.3 (2 × CH_Ar), 125.8 (q, J = 3.8 Hz, 2 × CH_Ar), 125.4 (C_q), 121.7 (d, J = 272.0 Hz, C_q), 114.3 (2 × CH_Ar), 106.1 (C_q), 55.4 (CH₃), 53.4 (CH₂), 50.9 (CH₂). ¹⁹F NMR (376 MHz, Chloroform-d): δ −62.31. IR (ATR diamond, cm⁻¹) ν: 2931, 2179, 1980, 1612, 1514, 1325, 1251, 1101, 1016, 925, 839, 694. HRMS (EI+) m/z calcd for C₂₆H₂₂F₃N₄O [M+H]⁺: 463.1740, found: 463.1741.

4.4.7. 4-Benzyl-1-(4-methoxybenzyl)-6-(thiophen-3-yl)1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (29)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (50 mg, 0.126 mmol, 1.0 eq.), 3-thienyl boronic acid (25 mg, 0.189 mmol, 1.5 eq.), potassium phosphate tribasic (54 mg, 0.253 mmol, 2.0 eq.), Pd (OAc)₂ (0.9 mg, 0.004 mmol, 0.03 eq.), and RuPhos (3.5 mg, 0.008 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 29 as a yellow oil (30 mg, 60%). R_f = 0.33 (PE/EtOAc: 70/30). ¹H NMR (400 MHz, Chloroform-d): δ 7.40–7.30 (m, 6H), 7.04 (m, 4H), 6.99 (s, 1H), 6.80 (d, J = 8.2 Hz, 2H), 5.68 (s, 2H), 5.30 (s, 2H), 3.76 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 151.2 (C_q), 136.7 (C_q), 133.6 (C_q), 129.0 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.2 (CH_Ar), 128.1 (C_q), 128.0 (2 × CH_Ar), 127.7 (CH_Ar), 127.5 (CH_Ar), 126.2 (C_q), 125.7 (C_q), 119.9 (CH_Ar), 114.2 (2 × CH_Ar), 102.0 (C_q), 55.3 (CH₃), 52.9 (CH₂), 50.7 (CH₂). IR (ATR diamond, cm⁻¹) ν: 2926, 2837, 1961, 1610, 1512, 1340, 1246, 1149, 1029, 848, 794, 648. HRMS (EI+) m/z calcd for C₂₃H₂₀N₄OS [M+H]⁺: 401.1431, found: 401.1433.

4.4.8. 4-(4-Benzyl-1-(4-methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazol-6-yl)phenol (30)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-Methoxybenzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 17 (70 mg, 0.18 mmol, 1.0 eq.), p-hydroxyphenyl boronic acid (37 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 30 as an orange solid (21 mg, 29%). R_f = 0.20 (PE/EtOAc: 70/30). Mp 175–177 °C. ¹H NMR (400 MHz, Acetone-d₆) δ 8.31 (bs, 1H), 7.42 (d, J = 7.0 Hz, 2H), 7.38–7.25 (m, 6H), 7.02 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 5.68 (s, 2H), 5.32 (s, 2H), 3.71 (s, 3H). ¹³C NMR (101 MHz, Acetone-d₆): δ 160.3 (C_q), 157.0 (C_q), 152.1 (C_q), 138.7 (C_q), 129.7 (C_q), 129.5 (4 × CH_Ar), 129.4 (2 × CH_Ar), 128.7 (2 × CH_Ar), 128.6 (CH_Ar), 128.1 (CH_Ar), 126.3 (C_q), 125.7 (C_q), 116.5 (2 × CH_Ar), 114.7 (2 × CH_Ar), 107.6 (C_q), 55.5 (CH₃), 53.4 (CH₂), 51.0 (CH₂). IR (ATR diamond, cm⁻¹) ν: 2952, 2924, 1612, 1512, 1249, 1175, 1029, 839, 779, 657. HRMS (EI+) m/z calcd for C₂₅H₂₃N₄O₂ [M+H]⁺: 411.1816, found: 411.1814.

4.4.9. 4-Benzyl-1-(thiophen-2-ylmethyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (31)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(thiophen-2-ylmethyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 19 (203 mg, 0.54 mmol, 1.0 eq.), p-tolyl boronic acid (111 mg, 0.82 mmol, 1.5 eq.), potassium phosphate tribasic (236 mg, 1.09 mmol, 2.0 eq.), Pd (OAc)₂ (3.7 mg, 0.02 mmol, 0.03 eq.), and RuPhos (16 mg, 0.03 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 31 as a yellow oil (191 mg, 91%). R_f = 0.18 (PE/EtOAc: 80/20). ¹H NMR (400 MHz, Chloroform-d): δ 7.35–7.25 (m, 7H), 7.20–7.15 (m, 3H), 6.96 (s, 1H), 6.86–6.82 (m, 1H), 6.81–6.78 (m, 1H), 5.86 (s, 2H), 5.29 (s, 2H), 2.37 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 151.4 (C_q), 138.3 (C_q), 136.8 (C_q), 136.4 (C_q), 130.4 (C_q), 129.7 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.2 (CH_Ar), 128.0 (2 × CH_Ar), 127.5 (CH_Ar), 127.4 (2 × CH_Ar), 127.0 (CH_Ar), 126.9 (CH_Ar), 126.2 (CH_Ar), 125.5 (C_q), 107.2 (C_q), 50.7 (CH₂), 48.5 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2927, 2156, 1535, 1514, 1435, 1344, 1232, 1180, 929, 852, 792, 748, 619, 578. HRMS (EI+) m/z calcd for C₂₃H₂₁N₄S [M+H]⁺: 385.1481, found: 385.1483.

4.4.10. 4-Benzyl-6-(p-tolyl)-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (32)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 18 (100 mg, 0.23 mmol, 1.0 eq.), p-tolyl boronic acid (48 mg, 0.34 mmol, 1.5 eq.), potassium phosphate tribasic (98 mg, 0.46 mmol, 2.0 eq.), Pd (OAc)₂ (1.6 mg, 0.007 mmol, 0.03 eq.), and RuPhos (6.5 mg, 0.014 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 32 as a white solid (85 mg, 83%). R_f = 0.36 (PE/EtOAc: 80/20). Mp 143–145 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.48 (d, J = 8.0 Hz, 2H), 7.38–7.28 (m, 5H), 7.18 (d, J = 8.0 Hz, 2H), 7.15–7.07 (m, 4H), 6.96 (s, 1H), 5.74 (s, 2H), 5.29 (s, 2H), 2.34 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 151.4 (C_q), 140.0 (C_q), 136.6 (C_q), 136.5 (C_q), 130.36 (d, J = 32.6 Hz, C_q), 130.1 (C_q), 129.6 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.3 (CH_Ar), 128.1 (2 × CH_Ar), 127.8 (2 × CH_Ar), 127.7 (CH_Ar), 127.3 (2 × CH_Ar), 125.9 (C_q), 125.8 (q, J = 3.8 Hz, 2 × CH_Ar), 124.0 (d, J = 272.2 Hz, C_q), 107.1 (C_q), 53.0 (CH₂), 50.8 (CH₂), 21.2 (CH₃). ¹⁹F NMR (376 MHz, Chloroform-d): δ −62.7. IR (ATR diamond, cm⁻¹) ν: 2916, 2848, 2160, 1512, 1325, 1159, 1112, 1066, 1016, 933, 823, 702, 628. HRMS (EI+) m/z calcd for C₂₆H₂₁F₃N₄ [M+H]⁺: 447.1791, found: 447.1793.

4.4.11. 4-Benzyl-1-isopropyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (33)

The reaction was carried out as described in general procedure C using 4-benzyl-6-bromo-1-isopropyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 20 (130 mg, 0.41 mmol, 1.0 eq.), p-tolyl boronic acid (84 mg, 0.61 mmol, 1.5 eq.), potassium phosphate tribasic (173 mg, 0.82 mmol, 2.0 eq.), Pd (OAc)₂ (2.7 mg, 0.012 mmol, 0.03 eq.), and RuPhos (11.4 mg, 0.0024 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 33 as a yellow oil (110 mg, 82%). R_f = 0.23 (PE/EtOAc: 80/20). ¹H NMR (400 MHz, Chloroform-d): δ 7.38–7.17 (m, 9H), 6.91 (s, 1H), 5.26 (s, 2H), 4.87 (hept, J = 6.8 Hz, 1H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz, 6H). ¹³C NMR (101 MHz, Chloroform-d): δ 151.1 (C_q), 136.9 (C_q), 136.3 (C_q), 130.8 (C_q), 129.5 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.0 (CH_Ar), 128.0 (2 × CH_Ar), 127.7 (2 × CH_Ar), 127.2 (CH_Ar), 125.3 (C_q), 106.9 (C_q), 52.7 (CH), 50.6 (CH₂), 22.8 (2 × CH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2981, 2920, 1573, 1535, 1512, 1452, 1348, 1174, 1157, 10101, 1028, 921, 821, 786. HRMS (EI+) m/z calcd for C₂₁H₂₃N₄ [M+H]⁺: 331.1917, found: 331.1915.

4.4.12. 1-(4-Methoxybenzyl)-4-methyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (34)

The reaction was carried out as described in general procedure C using 6-bromo-1-(4-Methoxybenzyl)-4-methyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 21 (58 mg, 0.18 mmol, 1.0 eq.), p-tolyl boronic acid (37 mg, 0.27 mmol, 1.5 eq.), potassium phosphate tribasic (76 mg, 0.36 mmol, 2.0 eq.), Pd (OAc)₂ (1.21 mg, 0.0054 mmol, 0.03 eq.), and RuPhos (5 mg, 0.011 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (1000/0) to 70/30) to afford 34 as a white solid (39 mg, 65%). R_f = 0.11 (PE/EtOAc: 70/30). Mp 115–117 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.19 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.92 (s, 1H), 6.75 (d, J = 8.7 Hz, 2H), 5.64 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 2.37 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 151.7 (C_q), 136.2 (C_q), 130.5 (C_q), 129.6 (2 × CH_Ar), 128.7 (2 × CH_Ar), 128.5 (CH_Ar), 128.3 (C_q), 127.4 (2 × CH_Ar), 125.6 (C_q), 114.2 (2 × CH_Ar), 106.6 (C_q), 55.4 (O-CH₃), 53.1 (CH₂), 33.2 (N-CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2160, 2015, 1612, 1514, 1249, 1190, 1049, 1018, 815, 754. HRMS (EI+) m/z calcd for C₂₀H₂₁N₄O [M+H]⁺: 333.1710, found: 333.1705.

4.5. General Procedure (D) for the Bromination of C-5 Position of C-6 Arylated 1,4-dihydropyrrolo[2,3-d][1,2,3]triazole Derivatives 35–39

To a solution of corresponding 1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative (1.0 eq.) in DCM (0.015 M) was added N-bromosuccinimide (1.0 eq.), and the mixture was stirred 1 h at room temperature. The resulting mixture was quenched using water and phases were separated. The aqueous phase was extracted with DCM and combined organic phases were washed with brine and dried over MgSO₄. After being concentrated under vacuum conditions, the residue was purified by flash chromatography on silica gel affording the desired bis 5-bromo-6-Aryl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative.

4.5.1. 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (35)

The reaction was carried out as described in general procedure D using 4-benzyl-1-(4-methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 22 (100 mg, 0.245 mmol, 1.0 eq.) and NBS (47 mg, 0.245 mmol, 1.0 eq.) in DCM (0.015 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 35 as a white solid (100 mg, 86%). R_f = 0.28 (PE/EtOAc: 70/30). Mp 127–129 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.43–7.36 (m, 2H), 7.36–7.24 (m, 3H), 7.20 (s, 4H), 6.86 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 5.45 (s, 2H), 5.40 (s, 2H), 3.73 (s, 3H), 2.41 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 149.2 (C_q), 137.4 (C_q), 136.6 (C_q), 129.8 (2 × CH_Ar), 129.3 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.0 (C_q), 128.9 (2 × CH_Ar), 128.1 (2 × CH_Ar), 128.0 (CH_Ar), 127.7 (C_q), 125.2 (C_q), 114.1 (2 × CH_Ar), 113.5 (C_q), 106.8 (C_q), 55.4 (CH₃), 52.8 (CH₂), 49.4 (CH₂), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2996, 1610, 1537, 1513, 1337, 1243, 1179, 833, 799. HRMS (EI+) m/z calcd for C₂₆H₂₄BrN₄O [M+H]⁺: 487.1128, found: 487.1126.

4.5.2. 4-Benzyl-5-bromo-6-(p-tolyl)-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3] triazole (36)

The reaction was carried out as described in general procedure D using 4-benzyl-6-(p-tolyl)-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 32 (85 mg, 0.19 mmol, 1.0 eq.), and NBS (36 mg, 0.19 mmol, 1.0 eq.) in DCM (0.015 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 36 as a white solid (80 mg, 80%). R_f = 0.45 (PE/EtOAc: 80/20). Mp 157–159 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.45–7.38 (m, 4H), 7.37–7.28 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.57 (s, 2H), 5.42 (s, 2H), 2.40 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 149.1 (C_q), 139.4 (C_q), 137.6 (C_q), 136.4 (C_q), 130.43 (d, J = 32.5 Hz, C_q), 129.7 (2 × CH_Ar), 129.4 (2 × CH_Ar), 128.9 (2 × CH_Ar), 128.8 (C_q), 128.1 (CH_Ar), 128.1 (2 × CH_Ar), 128.0, (2 × CH_Ar), 125.7 (q, J = 3.7 Hz, 2 × CH_Ar), 125.4 (C_q), 124.0 (d, J = 271.6 Hz, C_q), 113.9 (C_q), 106.7 (C_q), 52.7 (CH₂), 49.5 (CH₂), 21.4 (CH₃). ¹⁹F NMR (376 MHz, Chloroform-d): δ −62.7. IR (ATR diamond, cm⁻¹) ν: 2925, 2175, 1927, 1514, 1465, 1421, 1323, 1190, 933, 825, 792, 721. HRMS (EI+) m/z calcd for C₂₆H₂₀BrF₃N₄ [M+H]⁺: 525.0896, found: 525.0894.

4.5.3. 4-Benzyl-5-bromo-1-(thiophen-2-ylmethyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (37)

The reaction was carried out as described in general procedure D using 4-Benzyl-1-(thiophen-2-ylmethyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 31 (160 mg, 0.41 mmol, 1.0 eq.), and NBS (78 mg, 0.41 mmol, 1.0 eq.) in DCM (0.015 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 37 as a white solid (170 mg, 90%). R_f = 0.22 (PE/EtOAc: 90/10). Mp 128–130 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.42–7.36 (m, 2H), 7.34–7.23 (m, 7H), 7.16–7.13 (m, 1H), 6.83–6.74 (m, 1H), 6.63–6.58 (m, 1H), 5.69 (s, 2H), 5.41 (s, 2H), 2.42 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 149.1 (C_q), 137.6 (C_q), 137.5 (C_q), 136.5 (C_q), 129.7 (2 × CH_Ar), 129.5 (2 × CH_Ar), 129.0 (C_q), 128.9 (2 × CH_Ar), 128.1 (3 × CH_Ar), 127.2 (CH_Ar), 126.9 (CH_Ar), 126.4 (CH_Ar), 125.0 (C_q), 113.6 (C_q), 106.8 (C_q), 49.5 (CH₂), 47.9 (CH₂), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2162, 1980, 1514, 1460, 1334, 1182, 1056, 1029, 906, 831, 740, 665, 611, 590. HRMS (EI+) m/z calcd for C₂₃H₂₀BrN₄S [M+H]⁺: 463.0587, found: 463.0590.

4.5.4. 4-Benzyl-5-bromo-1-isopropyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (38)

The reaction was carried out as described in general procedure D using 4-Benzyl-1-isopropyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 33 (90 mg, 0.27 mmol, 1.0 eq.), and NBS (52 mg, 0.27 mmol, 1.0 eq.) in DCM (0.015 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 38 as a white solid (100 mg, 90%). R_f = 0.51 (PE/EtOAc: 80/20). Mp 127–129 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.48–7.42 (m, 2H), 7.38–7.26 (m, 7H), 5.45 (s, 2H), 4.74 (p, J = 6.7 Hz, 1H), 2.44 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H). ¹³C NMR (101 MHz, Chloroform-d): δ 148.9 (C_q), 137.5 (C_q), 136.7 (C_q), 130.0 (2 × CH_Ar), 129.6 (C_q), 129.4 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.1 (2 × CH_Ar), 128.0 (CH_Ar), 124.7 (C_q), 113.4 (C_q), 106.6 (C_q), 52.7 (CH₃), 49.4 (CH₂), 22.6 (2 × CH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3058, 2988, 1509, 1454, 1341, 1156, 1109, 1066, 788, 711. HRMS (EI+) m/z calcd for C₂₁H₂₂BrN₄ [M+H]⁺: 409.1022, found: 409.1024.

4.5.5. 5-bromo-1-(4-Methoxybenzyl)-4-methyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (39)

The reaction was carried out as described in general procedure D using 1-(4-Methoxybenzyl)-4-methyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 34 (60 mg, 0.18 mmol, 1.0 eq.) and NBS (34 mg, 0.18 mmol, 1.0 eq.) in DCM (0.015 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 39 as a white solid (70 mg, 95%). R_f = 0.33 (PE/EtOAc: 70/30). Mp 153–155 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.24–7.14 (m, 4H), 6.84 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 5.45 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 2.42 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 149.5 (C_q), 137.3 (C_q), 129.7 (2 × CH_Ar), 129.3 (2 × CH_Ar), 129.1 (C_q), 129.0 (2 × CH_Ar), 127.8 (C_q), 124.9 (C_q), 114.2 (C_q), 114.1 (2 × CH_Ar), 106.3 (C_q), 55.4 (O-CH₃), 52.8 (CH₂), 32.4 (N-CH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2160, 2015, 1612, 1514, 1249, 1190, 1049, 1018, 815, 764, 754. HRMS (EI+) m/z calcd for C₂₀H₂₀BrN₄O [M+H]⁺: 411.0815, found: 411.0813.

4.6. General Procedure (E): Suzuki–Miyaura Cross-Coupling in C-5 Position of 5-bromo-6-aryl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole Derivative 40–53

A solution of corresponding 5-bromo-6-aryl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole derivative (1.0 eq.), potassium phosphate tribasic (2.0 eq.), and corresponding aryl boronic acid (1.5 eq.) in dry 1,4-dioxane (0.15 M) was degassed by argon bubbling for 15 min. Pd (OAc)₂ (0.03 eq.) and RuPhos (0.06 eq.) were added and the mixture was heated at 120 °C for 1 h under microwave irradiation. The reaction mixture was filtered through a pad of celite, and the filtrate was reduced to dryness under vacuum. The residue was taken up in DCM, washed with water and dried over MgSO₄. After being concentrated under vacuum conditions, the residue was purified by flash chromatography on silica gel affording the desired 5,6-arylated 1,4-dihydropyrrolo[2,3-d][1,2,3] triazole derivative.

4.6.1. 4-Benzyl-1-(4-methoxybenzyl)-5,6-di-p-tolyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (40)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (80 mg, 0.16 mmol, 1.0 eq.), p-tolyl boronic acid (34 mg, 0.25 mmol, 1.5 eq.), potassium phosphate tribasic (70 mg, 0.33 mmol, 2.0 eq.), Pd (OAc)₂ (1.1 mg, 0.005 mmol, 0.03 eq.), and RuPhos (4.6 mg, 0.010 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 40 as a white solid (61 mg, 75%). R_f = 0.23 (PE/EtOAc: 70/30). Mp 125–127 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.25–7.17 (m, 3H), 7.13–7.03 (m, 6H), 7.00 (d, J = 7.8 Hz, 2H), 6.95–6.90 (m, 4H), 6.70 (d, J = 8.2 Hz, 2H), 5.52 (s, 2H), 5.19 (s, 2H), 3.72 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 140.4 (C_q), 138.4 (C_q), 137.7 (C_q), 135.9 (C_q), 131.1 (2 × CH_Ar), 130.3 (C_q), 129.8 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.1 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.3 (C_q), 128.0 (C_q), 127.6 (2 × CH_Ar), 127.5 (CH_Ar), 126.7 (C_q), 114.0 (2 × CH_Ar), 104.6 (C_q), 55.3 (CH₃), 52.6 (CH₂), 48.3 (CH₂), 21.5 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3028, 2927, 1509, 1513, 1329, 1244, 1179, 1049, 948, 924, 754. HRMS (EI+) m/z calcd for C₃₃H₃₁N₄O [M+H]⁺: 499.2492, found: 499.247.

4.6.2. 4-Benzyl-1-(4-methoxybenzyl)-5-(m-tolyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (41)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), m-tolyl boronic acid (17 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd (OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 41 as a white solid (40 mg, 97%). R_f = 0.35 (PE/EtOAc: 70/30). Mp 147–149 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.28–7.12 (m, 7H), 7.02 (d, J = 7.9 Hz, 2H), 7.00–6.92 (m, 6H), 6.74 (d, J = 8.6 Hz, 2H), 5.55 (s, 2H), 5.21 (s, 2H), 3.76 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 151.3 (C_q), 140.5 (C_q), 138.0 (C_q), 137.8 (C_q), 135.9 (C_q), 131.9 (CH_Ar), 130.9 (C_q), 130.3 (C_q), 129.8 (2 × CH_Ar), 129.3 (CH_Ar), 129.2 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.5 (CH_Ar), 128.3 (CH_Ar), 128.3 (C_q), 127.7 (2 × CH_Ar), 127.6 (CH_Ar), 126.7 (C_q), 114.0 (2 × CH_Ar), 104.7 (C_q), 55.4 (CH₃), 52.7 (CH₂), 48.5 (CH₂), 21.5 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2008, 1513, 1328, 1189, 1072, 983, 926, 783, 737, 589. HRMS (EI+) m/z calcd for C₃₃H₃₁N₄O [M+H]⁺: 499.2492, found: 499.2495.

4.6.3. 4-Benzyl-1-(4-methoxybenzyl)-5-(o-tolyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (42)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), o-tolyl boronic acid (17 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd (OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 42 as a white solid (36 mg, 88%). R_f = 0.45 (PE/EtOAc: 80/20). Mp 102–104 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.31–7.24 (m, 1H), 7.23–7.08 (m, 6H), 7.03–6.92 (m, 6H), 6.88 (d, J = 7.8 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 5.56 (q, ABX, 2H), 5.05 (s, 2H), 3.73 (s, 3H), 2.27 (s, 3H), 1.70 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 151.0 (C_q), 139.1 (C_q), 138.9 (C_q), 137.3 (C_q), 135.8 (C_q), 132.1 (CH_Ar), 130.5 (C_q), 130.4 (C_q), 130.3 (CH_Ar), 129.3 (CH_Ar), 129.2 (2 × CH_Ar), 129.1 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.5 (2 × CH_Ar), 128.2 (C_q), 128.1 (2 × CH_Ar), 127.6 (CH_Ar), 126.4 (C_q), 125.7 (CH_Ar), 114.0 (2 × CH_Ar), 105.1 (C_q), 55.3 (CH₃), 52.7 (CH₂), 48.2 (CH₂), 21.2 (CH₃), 19.7 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2162, 2046, 1992, 1517, 1436, 1253, 1186, 1031, 815, 698, 553. HRMS (EI+) m/z calcd for C₃₃H₃₁N₄O [M+H]⁺: 499.2492, found: 499.2491.

4.6.4. 4-(Benzyl-1-(4-Methoxybenzyl)-5-phenyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (43)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), phenyl boronic acid (15 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd (OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 43 as a white solid (30 mg, 76%). R_f = 0.30 (PE/EtOAc: 70/30). Mp 166–168 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.36–7.28 (m, 3H), 7.27–7.17 (m, 5H), 7.13–7.07 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 7.00–6.92 (m, 4H), 6.74 (d, J = 8.4 Hz, 2H), 5.56 (s, 2H), 5.23 (s, 2H), 3.76 (s, 3H), 2.33 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 151.3 (C_q), 140.2 (C_q), 137.6 (C_q), 136.0 (C_q), 131.3 (2 × CH_Ar), 131.0 (C_q), 130.2 (C_q), 129.8 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.5 (CH_Ar), 128.5 (2 × CH_Ar), 128.2 (C_q), 127.6 (2 × CH_Ar), 127.5 (CH_Ar), 126.7 (C_q), 114.0 (2 × CH_Ar), 104.9 (C_q), 55.4 (CH₃), 52.7 (CH₂), 48.4 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2960, 2160, 1610, 1514, 1354, 1249, 1193, 1028, 918, 771, 736. HRMS (EI+) m/z calcd for C₃₂H₂₉N₄O [M+H]⁺: 485.2336, found: 485.2367.

4.6.5. 4-(Benzyl-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (44)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), 4-methoxyphenyl boronic acid (19 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd (OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 44 as a white solid (35 mg, 83%). R_f = 0.17 (PE/EtOAc: 80/20). Mp 159–161 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.27–7.20 (m, 3H), 7.14–7.05 (m, 4H), 7.01 (d, J = 7.8 Hz, 2H), 6.98–6.91 (m, 4H), 6.82 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.2 Hz, 2H), 5.52 (s, 2H), 5.19 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 2.31 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.7 (C_q), 159.3 (C_q), 151.1 (C_q), 140.2 (C_q), 137.8 (C_q), 135.8 (C_q), 132.5 (2 × CH_Ar), 130.4 (C_q), 129.8 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.3 (C_q), 127.6 (2 × CH_Ar), 127.5 (CH_Ar), 126.7 (C_q), 123.2 (C_q), 114.0 (2 × CH_Ar), 113.9 (2 × CH_Ar), 104.6 (C_q), 55.3 (2 × CH₃), 52.6 (CH₂), 48.3 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2918, 2162, 2015, 1514, 1431, 1178, 1026, 815, 777, 731, 698. HRMS (EI+) m/z calcd for C₃₃H₃₁N₄O [M+H]⁺: 515.2441, found: 515.2443.

4.6.6. 4-(Benzyl-1-(4-methoxybenzyl)-6-(p-tolyl)- 5-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (45)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), 4-(trifluoromethyl)phenyl boronic acid (24 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd (OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 45 as a white solid (40 mg, 88%). R_f = 0.16 (PE/EtOAc: 80/20). Mp 135–137 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.53 (d, J = 8.0 Hz, 2H), 7.29–7.20 (m, 5H), 7.08–7.01 (m, 4H), 6.95–6.87 (m, 4H), 6.70 (d, J = 8.2 Hz, 2H), 5.52 (s, 2H), 5.21 (s, 2H), 3.73 (s, 3H), 2.33 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.4 (C_q), 151.7 (C_q), 138.4 (C_q), 137.3 (C_q), 136.6 (C_q), 134.8 (C_q), 131.5 (2 × CH_Ar), 130.4 (d, J = 32.6 Hz, C_q), 129.9 (2 × CH_Ar), 129.6 (C_q), 129.3 (2 × CH_Ar), 129.2 (2 × CH_Ar), 128.8 (2 × CH_Ar), 128.0 (C_q), 127.8 (CH_Ar), 127.4 (2 × CH_Ar), 126.6 (C_q), 125.4 (q, J = 3.5 Hz, C_q), 123.88 (d, J = 234.4 Hz, 2 × CH_Ar), 114.0 (2 × CH_Ar), 105.8 (C_q), 55.4 (CH₃), 52.7 (CH₂), 48.7 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2929, 2158, 1977, 1612, 1512, 1317, 1163, 1058, 817, 669. HRMS (EI+) m/z calcd for C₃₃H₂₈F₃N₄O [M+H]⁺: 553.2210, found: 553.2211.

4.6.7. 4-(Benzyl-1-(4-methoxybenzyl)-5-(4-nitrophenyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (46)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), 4-nitrophenyl boronic acid (21 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd (OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.8 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 46 as a white solid (21 mg, 48%). R_f = 0.19 (PE/EtOAc: 80/20). Mp 77–79 °C. ¹H NMR (400 MHz, Chloroform-d): δ 8.13 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.25–7.24 (m, 3H), 7.10–7.04 (m, 4H), 6.91 (m, 4H), 6.73 (d, J = 8.2 Hz, 2H), 5.54 (s, 2H), 5.28 (s, 2H), 3.76 (s, 3H), 2.36 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.5 (C_q), 152.2 (C_q), 147.4 (C_q), 137.8 (C_q), 137.5 (C_q), 137.1 (C_q), 137.0 (C_q), 131.9 (2 × CH_Ar), 130.0 (2 × CH_Ar), 129.5 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.2 (C_q), 128.9 (2 × CH_Ar), 128.0 (CH_Ar), 127.8 (2 × C_q), 127.2 (2 × CH_Ar), 126.7 (C_q), 123.7 (2 × CH_Ar), 114.1 (2 × CH_Ar), 106.7 (C_q), 55.4 (CH₃), 52.8 (CH₂), 48.9 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2922, 2850, 2160, 1598, 1344, 1246, 1176, 1029, 802. HRMS (EI+) m/z calcd for C₃₃H₂₈N₅O₃ [M+H]⁺: 530.2187, found: 530.2186.

4.6.8. 4-(Benzyl-1-(4-methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazol-5-yl)phenol (47)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), 4-hydroxyphenyl boronic acid (17 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd(OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 47 as a white solid (20 mg, 49%). R_f = 0.08 (PE/EtOAc: 80/20). Mp 195–197 °C. ¹H NMR (400 MHz, Acetone-d₆): δ 8.69 (bs, 1H), 7.26–7.17 (m, 3H), 7.13–7.02 (m, 8H), 6.90 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 8.3 Hz, 2H), 5.55 (s, 2H), 5.22 (s, 2H), 3.71 (s, 3H), 2.29 (s, 3H). ¹³C NMR (101 MHz, Acetone-d₆): δ 160.3 (C_q), 158.7 (C_q), 151.7 (C_q), 141.0 (C_q), 139.0 (C_q), 136.4 (C_q), 133.4 (2 × CH_Ar), 131.5 (C_q), 130.6 (2 × CH_Ar), 129.8 (2 × CH_Ar), 129.7 (2 × CH_Ar), 129.5 (C_q), 129. (2 × CH_Ar), 128.2 (CH_Ar), 128.1 (2 × CH_Ar), 127.1 (C_q), 122.8 (C_q), 116.2 (2 × CH_Ar), 114.6 (2 × CH_Ar), 105.2 (C_q), 55.5 (CH₃), 53.0 (CH₂), 48.6 (CH₂), 21.1 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2177, 2031, 1971, 1612, 1454, 1064, 1026, 927, 794, 759, 723, 696. HRMS (EI+) m/z calculated for C₃₂H₂₉N₄O₂ [M+H]⁺: 501.2285, found: 501.2285.

4.6.9. 4-Benzyl-1-(4-methoxybenzyl)-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazol-5-yl) (48)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), 4-(2-tetrahydropyranyloxy)phenylboronic acid (27 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd(OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 48 as a white solid (46 mg, 96%). R_f = 0.10 (PE/EtOAc: 80/20). Mp 167–169 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.28–7.17 (m, 3H), 7.17–7.04 (m, 4H), 7.04–6.89 (m, 8H), 6.71 (d, J = 8.3 Hz, 2H), 5.52 (s, 2H), 5.39 (m, 1H), 5.19 (s, 2H), 3.92 (m, 1H), 3.73 (s, 3H), 3.62 (m, 1H), 2.31 (s, 3H), 1.99 (m, 1H), 1.86 (m, 2H), 1.71–1.57 (m, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 157.3 (C_q), 151.0 (C_q), 140.2 (C_q), 137.7 (C_q), 135.8 (C_q), 132.4 (2 × CH_Ar), 130.3 (C_q), 129.8 (2 × CH_Ar), 129.1 (2 × CH_Ar), 129.0 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.3 (C_q), 127.6 (2 × CH_Ar), 127.5 (CH_Ar), 126.7 (C_q), 124.0 (C_q), 116.3 (2 × CH_Ar), 114.0 (2 × CH_Ar), 104.6 (C_q), 96.6 (CH), 62.5 (CH₂), 55.3 (CH₃), 52.6 (CH₂), 48.3 (CH₂), 30.5 (CH₂), 25.2 (CH₂), 21.3 (CH₃), 19.0 (CH₂). IR (ATR diamond, cm⁻¹) ν: 2941, 2166, 1608, 1514, 1467, 1244, 1172, 1020, 918, 817. HRMS (EI+) m/z calcd for C₃₇H₃₇N₄O₃ [M+H]⁺: 585.2860, found: 585.2862.

4.6.10. 4-Benzyl-1-(4-methoxybenzyl)-5-(thiophen-3-yl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3] triazole (49)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(4-Methoxybenzyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 35 (40 mg, 0.08 mmol, 1.0 eq.), 3-thienyl boronic acid (16 mg, 0.12 mmol, 1.5 eq.), potassium phosphate tribasic (35 mg, 0.16 mmol, 2.0 eq.), Pd(OAc)₂ (0.67 mg, 0.003 mmol, 0.03 eq.), and RuPhos (2.80 mg, 0.006 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 49 as a white solid (22 mg, 55%). R_f = 0.27 (PE/EtOAc: 80/20). Mp 121–123 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.28–7.20 (m, 4H), 7.13 (d, J = 7.2 Hz, 2H), 7.05 (m, 3H), 6.97–6.90 (m, 4H), 6.81 (d, J = 5.0 Hz, 1H), 6.71 (d, J = 8.3 Hz, 2H), 5.52 (s, 2H), 5.25 (s, 2H), 3.73 (s, 3H), 2.33 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 151.2 (C_q), 137.8 (C_q), 136.2 (C_q), 135.0 (C_q), 131.2 (C_q), 130.2 (C_q), 129.7 (2 × CH_Ar), 129.5 (CH_Ar), 129.1 (2 × CH_Ar), 129.1 (2 × CH_Ar), 128.7 (2 × CH_Ar), 128.2 (C_q), 127.6 (CH_Ar), 127.4 (2 × CH_Ar), 126.5 (CH_Ar), 126.5 (C_q), 125.8 (CH_Ar), 114.0 (2 × CH_Ar), 105.2 (C_q), 55.3 (CH₃), 52.7 (CH₂), 48.4 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹): δ 159.3 (C_q), 151.2 (C_q), 137.8 (C_q), 136.2 (C_q), 135.0 (C_q), 131.2 (C_q), 130.2 (C_q), 129.7 (2 × CH_Ar), 129.5 (CH_Ar), 129.1 (2 × CH_Ar), 129.1 (2 × CH_Ar), 128.7 (2 × CH_Ar), 128.2 (C_q), 127.6 (CH_Ar), 127.4 (2 × CH_Ar), 126.5 (CH_Ar), 126.5 (C_q), 125.8 (CH_Ar), 114.0 (2 × CH_Ar), 105.2 (C_q), 55.3 (CH₃), 52.7 (CH₂), 48.4 (CH₂), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2929, 2158, 1982, 1612, 1514, 1327, 1249, 1182, 1029, 788, 752, 696, 640. HRMS (EI+) m/z calcd for C₃₀H₂₇N₄OS [M+H]⁺: 491.1900, found: 491.1803.

4.6.11. 4-Benzyl-1-(thiophen-2-ylmethyl)-5,6-di-p-tolyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (50)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-(thiophen-2-ylmethyl)-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 37 (100 mg, 0.22 mmol, 1.0 eq.), p-tolyl boronic acid (46 mg, 0.33 mmol, 1.5 eq.), potassium phosphate tribasic (94 mg, 0.44 mmol, 2.0 eq.), Pd(OAc)₂ (1.5 mg, 0.007 mmol, 0.03 eq.), and RuPhos (6.2 mg, 0.013 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 50 as a white solid (100 mg, 96%). R_f = 0.33 (PE/EtOAc: 80/20). Mp 158–160 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.25–6.99 (m, 14H), 6.83–6.78 (m, 1H), 6.66–6.63 (m, 1H), 5.76 (s, 2H), 5.19 (s, 2H), 2.35 (s, 3H), 2.32 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 151.1 (C_q), 140.6 (C_q), 138.5 (C_q), 138.3 (C_q), 137.7 (C_q), 136.0 (C_q), 131.1 (2 × CH_Ar), 130.4 (C_q), 129.7 (2 × CH_Ar), 129.3 (2 × CH_Ar), 129.2 (2 × CH_Ar), 128.6 (2 × CH_Ar), 127.9 (C_q), 127.6 (2 × CH_Ar), 127.6 (CH_Ar), 127.1 (CH_Ar), 126.9 (CH_Ar), 126.5 (C_q), 126.2 (CH_Ar), 104.7 (C_q), 48.4 (CH₂), 47.8 (CH₂), 21.5 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2978, 1512, 1496, 1454, 1344, 1178, 1145, 1126, 1062, 923, 729, 680. HRMS (EI+) m/z calcd for C₃₀H₂₇N₄S [M+H]⁺: 475.1951, found: 475.1955.

4.6.12. 4-Benzyl-5,6-di-p-tolyl-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (51)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-6-(p-tolyl)-1-(4-(trifluoromethyl)benzyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 36 (60 mg, 0.114 mmol, 1.0 eq.), p-tolyl boronic acid (24 mg, 0.171 mmol, 1.5 eq.), potassium phosphate tribasic (49 mg, 0.228 mmol, 2.0 eq.), Pd(OAc)₂ (0.8 mg, 0.003 mmol, 0.03 eq.), and RuPhos (3.2 mg, 0.007 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 51 as a white solid (41 mg, 70%). R_f = 0.36 (PE/EtOAc: 70/30). Mp 177–179 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.43 (d, J = 8.0 Hz, 2H), 7.25–7.18 (m, 3H), 7.09 (m, 8H, H-9), 6.97 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 7.8 Hz, 2H), 5.63 (s, 2H), 5.21 (s, 2H), 2.34 (s, 3H), 2.29 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 151.2 (C_q), 140.8 (C_q), 140.0 (C_q), 138.6 (C_q), 137.6 (C_q), 136.1 (C_q), 131.1 (2 × CH_Ar), 130.1 (C_q), 129.9 (d, J = 29.6 Hz, C_q), 129.7 (2 × CH_Ar), 129.3 (2 × CH_Ar), 129.1 (2 × CH_Ar), 128.7 (2 × CH_Ar), 128.0 (2 × CH_Ar), 127.8 (C_q), 127.6 (3 × CH_Ar), 126.9 (C_q), 125.6 (q, J = 3.7 Hz, 2 × CH_Ar), 124.1 (d, J = 272.1 Hz, C_q), 104.6 (C_q), 52.6 (CH₂), 48.4 (CH₂), 21.5 (CH₃), 21.2 (CH₃). ¹⁹F NMR (376 MHz, Chloroform-d): δ −62.7. IR (ATR diamond, cm⁻¹) ν: 2196, 2025, 1514, 1323, 1122, 1066, 931, 794, 678, 586. HRMS (EI+) m/z calcd for C₃₃H₂₇F₃N₄ [M+H]⁺: 537.2260, found: 537.2262.

4.6.13. 4-Benzyl-1-isopropyl-5,6-di-p-tolyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (52)

The reaction was carried out as described in general procedure E using 4-Benzyl-5-bromo-1-isopropyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 38 (70 mg, 0.171 mmol, 1.0 eq.), p-tolyl boronic acid (35 mg, 0.257 mmol, 1.5 eq.), potassium phosphate tribasic (73 mg, 0.342 mmol, 2.0 eq.), Pd(OAc)₂ (1.2 mg, 0.005 mmol, 0.03 eq.), and RuPhos (4.8 mg, 0.01 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (80/20) to afford 52 as a white solid (56 mg, 78%). R_f = 0.51 (PE/EtOAc: 80/20). Mp 137–139 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.26–7.01 (m, 13H), 5.20 (s, 2H), 4.78 (p, J = 6.7 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H). ¹³C NMR (101 MHz, Chloroform-d): δ 150.9 (C_q), 140.3 (C_q), 138.3 (C_q), 137.8 (C_q), 136.0 (C_q), 131.2 (2 × CH_Ar), 130.8 (C_q), 130.0 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.1 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.1 (C_q), 127.7 (2 × CH_Ar), 127.5 (CH_Ar), 126.3 (C_q), 104.6 (C_q), 52.4 (CH), 48.4 (CH₂), 22.7 (2 × CH₃), 21.5 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹): δ 150.9 (C_q), 140.3 (C_q), 138.3 (C_q), 137.8 (C_q), 136.0 (C_q), 131.2 (2 × CH_Ar), 130.8 (C_q), 130.0 (2 × CH_Ar), 129.2 (2 × CH_Ar), 129.1 (2 × CH_Ar), 128.6 (2 × CH_Ar), 128.1 (C_q), 127.7 (2 × CH_Ar), 127.5 (CH_Ar), 126.3 (C_q), 104.6 (C_q), 52.4 (CH), 48.4 (CH₂), 22.7 (2 × CH₃), 21.5 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2980, 2160, 1514, 1350, 1199, 1165, 1103, 952, 845, 777, 669. HRMS (EI+) m/z calcd for C₂₈H₂₉N₄ [M+H]⁺: 421.2387, found: 421.2390.

4.6.14. 1-(4-Methoxybenzyl)-4-methyl-5,6-di-p-tolyl-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole (53)

The reaction was carried out as described in general procedure E using 5-bomo-1-(4-Methoxybenzyl)-4-methyl-6-(p-tolyl)-1,4-dihydropyrrolo[2,3-d][1,2,3]triazole 39 (50 mg, 0.12 mmol, 1.0 eq.), p-tolyl boronic acid (25 mg, 0.18 mmol, 1.5 eq.), potassium phosphate tribasic (52 mg, 0.24 mmol, 2.0 eq.), Pd(OAc)₂ (0.8 mg, 0.004 mmol, 0.03 eq.), and RuPhos (3.3 mg, 0.007 mmol, 0.06 eq.) in dry 1,4-dioxane (0.15 M). The crude mixture was purified by flash chromatography on silica gel using (PE/EtOAc) from (100/0) to (70/30) to afford 53 as a white solid (48 mg, 95%). R_f = 0.33 (PE/EtOAc: 70/30). Mp 179–181 °C. ¹H NMR (400 MHz, Chloroform-d): δ 7.18–7.10 (m, 4H), 7.01 (d, J = 7.9 Hz, 2H), 6.96–6.88 (m, 4H), 6.71 (d, J = 8.7 Hz, 2H), 5.52 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H). ¹³C NMR (101 MHz, Chloroform-d): δ 159.3 (C_q), 140.4 (C_q), 138.3 (C_q), 135.9 (C_q), 130.9 (2 × CH_Ar), 130.5 (C_q), 129.9 (2 × CH_Ar), 129.3 (2 × CH_Ar), 129.1 (4 × CH_Ar), 128.3 (C_q), 128.0 (C_q), 126.4 (C_q), 114.0 (2 × CH_Ar), 55.4 (CH₃), 52.6 (CH₂), 31.6 (CH₃), 21.5 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2922, 1610, 1512, 1390, 1247, 1176, 1033, 1020, 775, 682. HRMS (EI+) m/z calcd for C₂₇H₂₇N₄O [M+H]⁺: 423.2179, found: 423.2178.