External base-free electrophilic diynylation of thiols with diynyl benziodoxolone

Abstract

In this study, external base-free electrophilic diynylation of thiols to 1,3-butadiynyl sulfide, an important structural motif in organic synthesis, chemical biology, and materials science using triisopropylsilyl diynyl benziodoxolone at room temperature has been developed. Various thiols, such as cysteine and thioglucopyranose derivatives and captopril, were converted into the corresponding 1,3-butadiynyl sulfides. Control experiments and a computational study were performed to investigate the reaction mechanism. The resulting 1,3-butadiynyl sulfides were further derivatized to thiobitriazole via double azide–alkyne cycloaddition and to cyclobutene via [2 + 2] cycloaddition.

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Thiols play diverse roles in biological systems, such as antioxidants in detoxification, protein function regulation, and signal transduction.¹ Their relatively high acidity and nucleophilicity make them suitable functional groups for various site-selective bioconjugation and labeling techniques, such as alkylation, alkenylation, alkynylation, arylation, and thiol–disulfide exchange reactions (Scheme 1A).² Waser (2013) reported a highly chemoselective alkynylation of thiols with triisopropylsilyl ethynyl benziodoxolone (TIPS-EBX), which is a highly reactive electrophilic alkynylation reagent, in the presence of 1,1,3,3-tetramethylguanidine as a base (Scheme 1B-a).³ This reaction, along with its broad substrate scope and high chemoselectivity, has practical applications in cysteine functionalization in peptides and proteins, even in living cells.⁴ Such reactions typically require a stoichiometric amount of a base or a basic buffer despite using a highly reactive hypervalent λ³-iodane.^5,6 In the absence of a base, disulfide is considered as the major product. Interestingly, when using a sulfonate-substituted EBX reagent, triisopropylsilyl ethynylation of glutathione proceeds in water without a base, likely because the electron-withdrawing sulfonate group (SO₃⁻: σ_p = 0.35) enhances EBX reactivity (Scheme 1B-b).^4f,7 However, tetradecyl-substituted EBX exhibits a low yield. Hypervalent λ³-bromane enables external base-free alkynylation of 2-mercapto-1,3-benzazoles; however, alkynyl hypervalent λ³-bromane is difficult to obtain owing to synthetic challenges (Scheme 1C).^8,9 A key motif in organic synthesis and materials science, 1,3-butadiynyl sulfide, has been used as a building block for organometallic molecular wires, polymers and heterocycles, such as triazole rings via azide–alkyne cycloaddition.¹⁰ However, synthetic methods for 1,3-butadiynyl sulfides are limited; therefore, their full potential as a building block is restricted. Reported approaches include cross-coupling, nucleophilic diynylation, and multistep reactions for synthesizing 1,3-butadiynyl sulfides, necessitating transition metals and/or strong bases (Scheme 1D-a,b,c).^10,11 A complementary electrophilic method is highly desirable for directly introducing a diyne to thiols, a feature particularly advantageous in chemical biology. Direct diynylation of thiols is rare. Stang (1990) reported diynylation of sodium thiolate with diynyl bis-iodonium salts at −30 °C (Scheme 1D-d and E).¹²

Scheme 1 Previous and this works.

Driven by our interest in developing hypervalent iodine compounds and by the utility of 1,3-butadiyne in various fields,^13,14 we recently reported triisopropylsilyl diynyl benziodoxolone (TIPS-diyne-BX) and copper-catalyzed electrophilic diynylation of sulfonamides using TIPS-diyne-BX.^13a,b Structurally, TIPS-diyne-BX is a strong candidate for direct electrophilic diynylation of thiols under mild reaction conditions owing to the electron-withdrawing nature of the alkyne group (H–C≡C: χ = 2.789, σ_p = 0.23; σ_p⁻ = 0.53).^7,15 This property likely stabilizes the transition state of α-addition of thiols, as suggested by Waser's mechanistic investigations (Scheme 1F).^4d Furthermore, conjugation between the alkyne and ethynyl benziodoxolone likely lowers the lowest unoccupied molecular orbital (LUMO) energy of the EBX reagent,¹⁶ enhancing its reactivity without altering benziodoxolone, the leaving group. Herein, we report an external base-free electrophilic diynylation of thiols (Scheme 1F).

The reaction conditions for electrophilic diynylation of thiols using 4-bromobenzenethiol (1a) and TIPS-diyne-BX (2a) are summarized in Tables 1 and S1–S3, SI. Using tetramethylguanidine (TMG) as a base in THF, 1,3-butadiynyl sulfide 3a was obtained with a yield of 69%, with disulfide 4a (20%) as a minor product (entry 1).³ The investigation of additives and solvents (entries 2–11) revealed that the highest yield (81%) was achieved using Et₃N as the base and EtOAc as the solvent (entry 7, Condition A). Notably, the reaction exhibited a good yield with a catalytic amount of Et₃N (entry 8) and even in the presence of acetic acid, albeit with a modest yield (entry 11). A moderate yield of 3a (41%) was obtained in the absence of any additive (entry 12). This prompted an investigation into solvent effects without additives, which revealed that acetone afforded 3a in 79% yield, with disulfide 4a (13%) as a minor product, at room temperature (entry 16, Condition B). This reaction could be carried out under air and in wet acetone without any loss of efficiency (entries 17 and 18). Remarkably, it was completed within 5 min owing to the absence of 2a in the ¹H NMR spectrum when acetone-d₆ was used as the solvent (entry 19).

Table 1 Study of reaction conditions^a

Entry	Additive	Solvent	Yield (%)
			3a	4a
a Reaction conditions: 1a (0.05 mmol), 2a (1.1 equiv.), additive (1.2 equiv.), dried solvent (2 mL), rt, 30 min, argon. ^1H NMR yields. Numbers in parentheses are isolated yields. b Et3N (0.2 equiv.) was used instead of Et3N (1.2 equiv.). c Under air. d Nondried acetone was used. e Reaction conditions: 1a (0.015 mmol), 2a (1.1 equiv.), acetone-d6 (0.6 mL), rt, <5 min, air.
1	TMG	THF	69	20
2	TMG	DCM	51	15
3	TMG	Acetone	59	16
4	TMG	EtOH	69	22
5	TMG	EtOAc	71	14
6	DBU	EtOAc	67	15
7	Et 3 N	EtOAc	79 (81)	17 (19)
8^b	Et3N	EtOAc	72	15
9	K2CO3	EtOAc	72	16
10	NaHCO3	EtOAc	47	48
11	AcOH	EtOAc	34	45
12	—	EtOAc	41	38
13	—	EtOH	41	25
14	—	DCM	44	28
15	—	THF	54	27
16	—	Acetone	80 (79)	15 (13)
17^c	—	Acetone	78	22
18^d	—	Acetone	76	21
19^e	—	Acetone-d6	(64)	(10)

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With optimized conditions in hand, we examined the scope and limitations using various thiols (Scheme 2). para-Substituted benzenethiols bearing electron-donating or electron-withdrawing groups afforded the desired 1,3-butadiynyl sulfides in good yields (3b–3d). 2-Bromobenzenethiol also gave the product in good yield (3e). 7-Mercapto-4-methylcoumarin (1f), a heteroaryl thiol, provided the corresponding product in moderate isolated yield (3f). Meanwhile, 2-mercaptobenzoxazole (1g) provided product 3g in modest yield. Notably, 3g was obtained in lower yield (11%) under Condition A than under Condition B (39%). Primary and secondary aliphatic thiols delivered the desired sulfides in modest to good yields (3h–3k). In the case of 3j, formation of the disulfide product 4j (42%) was also observed, as revealed by the ¹H NMR spectrum of the crude product. Under Condition A, 3i and 3j were obtained in the improved yields of 79% and 57%, respectively. The reaction of 1,2-ethanedithiol afforded the bis-1,3-butadiynyl sulfide 3l in high yield with 2.2 equivalents of 2a. More complex thiols were also compatible. A protected cysteine derivative yielded 3m in 81% yield, which increased to 89% on a 1 mmol scale, demonstrating the scalability of the method. Tetra-O-acetyl-1-thio-β-D-glucopyranose gave 3n in 55% yield, and captopril underwent diynylation in a mixed aqueous solvent (THF/H₂O = 14 : 1) to afford 3o in modest isolated yield. These results highlight the versatility of the method, as hydroxy, carboxyl, carbamate, ester, and certain heterocyclic functionalities were well tolerated. However, 2-quinoline thiol, 2-(diethylamino)ethanethiol hydrochloride, and thiobenzoic acid provided a complex mixture, as observed in the ¹H NMR spectrum, from which no products could be isolated, likely due to product instability (3p–3r).¹⁷

Scheme 2 Study of the substrate scope. Reaction conditions (Condition B): 1 (0.05 mmol), 2a (1.1 equiv.), acetone (2 mL), rt, 30 min, argon. Isolated yields. Numbers in parentheses are ¹H NMR yields. ^a 2a (2.2 equiv.) was used. ^b 1 mmol scale. ^c THF/H₂O (2 mL, 14 : 1) was used instead of acetone. ^d 2-(Diethylamino)ethanethiol hydrochloride was used as a substrate. ^e Condition A [1 (0.05 mmol), 2a (1.1 equiv.), Et₃N (1.2 equiv.), EtOAc (2 mL), rt, 30 min, argon] was used instead of Condition B. ^f Disulfide (4j: ^cHex–S–S–^cHex, 42%) was observed in the ¹H NMR spectrum of the crude product. ^g Disulfide (4j: ^cHex–S–S–^cHex, 10%) was observed in the ¹H NMR spectrum of the crude product.

To probe the reaction mechanism, a series of control experiments were conducted (Table 2). Diynylation of 1h proceeded to provide 3h in a good yield under dark conditions using Conditions A and B (entries 3 and 4). By contrast, the presence of the radical scavenger 2,6-di-tert-butyl-p-cresol (BHT) under Condition B decreased the yield (54%) (entry 6), suggesting the involvement of a radical intermediate. Similarly, 4-bromobenzenethiol (1a) showed a reduced yield under dark conditions and in the presence of BHT with Condition B (Table S4, SI). By contrast, the cysteine derivative 1m showed consistent yields under all tested conditions (Table S5, SI). These results reveal that the reaction proceeds via an ionic mechanism under Condition A, whereas it proceeds predominantly via an ionic pathway with a partial contribution from a radical pathway for certain substrates under Condition B.

Table 2 Control experiments^a

Entry	Conditions	Yield (%)
		3h	4h
a Reaction conditions: Condition A: 1h (0.05 mmol), 2a (1.1 equiv.), Et3N (1.2 equiv.), EtOAc (2 mL), rt, 30 min, argon. Condition B: 1h (0.05 mmol), 2a (1.1 equiv.), acetone (2 mL), rt, 30 min, argon. ^1H NMR yields. The number in parentheses is the isolated yield.
1	A	81	10
2	B	79 (82)	6
3	A, under dark	67	6
4	B, under dark	72	5
5	A, with BHT (1.0 equiv.)	73	8
6	B, with BHT (1.0 equiv.)	54	7

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To investigate the high reactivity of 2a in the absence of a base, various EBX reagents were evaluated under our reaction conditions (Table 3). TIPS-EBX (2b) afforded the corresponding product 3hb in low yield under both reaction conditions, with disulfide 4h as the major product (entries 3 and 4). Other electron-rich and neutral EBX reagents showed similar trends, producing lower yields of the corresponding thioalkynes (3hc–3he) without a base (entries 5–10). In contrast, 4-nitrophenyl-EBX gave the product in good yields even without a base (3hf: 81% and 67%) (entries 11 and 12).

Table 3 Reaction with various EBX reagents^a

Entry	R	Conditions	Yield (%)
			3	4h
a Reaction conditions: Condition A: 1h (0.05 mmol), 2 (1.1 equiv.), Et3N (1.2 equiv.), EtOAc (2 mL), rt, 30 min, argon. Condition B: 1h (0.05 mmol), 2 (1.1 equiv.), acetone (2 mL), rt, 30 min, argon. ^1H NMR yields. Number in parentheses is isolated yield.
1	TIPS-C≡C (2a)	A	3h: 81	10
2		B	3h: 79 (82)	6
3	TIPS (2b)	A	3hb: 29	61
4		B	3hb: 2	86
5	^nBu (2c)	A	3hc: 50	32
6		B	3hc: 19	74
7	4-MeO-C6H4 (2d)	A	3hd: 40	47
8		B	3hd: 12	78
9	Ph (2e)	A	3he: 23	65
10		B	3he: 17	59
11	4-NO2-C6H4 (2f)	A	3hf: 81	7
12		B	3hf: 67	9

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To further understand the high reactivity of 2a, DFT calculations were performed on a series of the EBX reagents to analyze their LUMO energies and natural population charges. Notably, 2a exhibited a low LUMO energy (−0.03187 a.u.) (Fig. 1). The LUMO, comprising the I–C σ* orbital (σ-hole) of the hypervalent iodine center and the π* orbital of the diyne moiety, is mainly localized on the iodine atom and the α-carbon (Fig. 2). Among the EBX reagents studied, 2a showed the highest δ⁺ character at the iodine atom and the lowest δ⁻ character at the α-carbon. These electronic features suggest that thiol coordination to the iodine atom and α-addition are both facilitated. The electron-withdrawing nature of the alkynyl group likely accounts for this charge distribution and the enhanced reactivity (H–C≡C: χ = 2.789, σ_p = 0.23, σ_p⁻ = 0.53) (Fig. 1).^7,15 In addition, the low steric crowding around the iodine and α-carbon atoms in 2a owing to the presence of two adjacent alkynyl groups may explain the higher yield obtained with 2a than that with 2f, which has a planar 4-nitro-phenyl group. Waser previously reported that acyl-substituted EBX reagents (acyl-EBX), which contain a strongly electron-withdrawing acyl group (PhCO: σ_p = 0.43, σ_p⁻ = 0.83) at the β-carbon, are unstable; thiols react with in situ-generated acyl-EBX to give ketene dithioarylacetals in the presence of a base.¹⁸

Fig. 1 LUMO energy (a.u.) and natural charge of alkynyl benziodoxolones.

Fig. 2 Molecular orbital and total SCF density of LUMO of 2a.

According to these results and previous reports, a plausible mechanism for the external base-free electrophilic diynylation of thiols is proposed (Scheme 3).^3,4 The thiol coordinates to the iodine center of TIPS-diyne-BX (2a) without a base in the presence of the high δ⁺ character of the iodine atom to provide complex A. Ligand exchange produces intermediate Bvia proton transfer. The electron-withdrawing alkynyl group favors α-addition over β-addition, leading to intermediate DviaC, with the stabilization of the δ⁻ character in C and D. Notably, vinyl benziodoxolone (S3h), likely formed via β-addition, was absent when a catalytic amount of Cs₂CO₃ was used in EtOH (Scheme S1, SI). Intermediate D undergoes β-elimination to afford product 3. However, the addition of the thiol to the α-carbon of 2a to the product through a single transition state without intermediates such as B and D, which were previously proposed for the reaction mechanism in the presence of a base, cannot be ruled out.^4d Control experiments indicate that although the reaction generally follows an ionic pathway, some substrates may partially proceed via a radical mechanism under certain conditions.¹⁹

Scheme 3 Plausible reaction mechanism.

To demonstrate the synthetic utility of 1,3-butadiynyl sulfides, we explored chemoselective azide–alkyne cycloaddition at the thioalkyne site, using cysteine-derived compound 3m and glycine-derived azide 5a under various conditions.^10a,13a,20 Optimal conditions were achieved with Cp*RuCl(cod) in MeCN at room temperature, affording 6a in good yield (Scheme 4 and Table S6, SI). This protocol was applied to the synthesis of 5-thiotriazoles containing N-acetylglucosamine, nucleoside, and pyrene moieties, delivering 6b–6d in good to high yields. Deprotection of the TIPS group in 6a afforded 7 in good yield, which subsequently underwent copper-catalyzed azide–alkyne cycloaddition with leucine-derived azide 8 to furnish thiobitriazole 9, a novel tripeptide analog, in 79% yield (Scheme 5).²¹ Furthermore, [2 + 2] cycloaddition with norbornadiene (10) in the presence of Cp*RuCl(cod) yielded cyclobutene 11 in high yield with a 1 : 1 diastereomeric ratio.²²

Scheme 4 RuAAC with 1,3-butadiynyl sulfide. Reaction conditions: 3m (1.1 equiv.), 5 (0.05 mmol.), Cp*RuCl(cod) (4 mol%), MeCN (1 mL), rt, 18 h, argon. Isolated yields.

Scheme 5 Derivatization of 1,3-butadiyne sulfide. ^a Reaction conditions: 6a (1.3 mmol), TBAF (2.0 equiv.), AcOH (3.0 equiv.), THF (1 mL), rt, 5 min, air. ^b 7 (1.1 equiv.), 8 (0.05 mmol), CuI (0.5 equiv.), DIPEA (1.1 equiv.), DCM (3 mL), rt, 17 h. ^c  3m (0.1 mmol), 10 (3.0 equiv.), Cp*RuCl(cod) (10 mol%), THF (0.5 mL), 90 °C, 24 h, dark. Isolated yields. The diastereomeric ratio (d.r.) was determined via¹H NMR spectroscopy.

Conclusions

Herein, we developed direct electrophilic diynylation of thiols using triisopropylsilyl diynyl benziodoxolone, which operates under mild conditions (no external base, room temperature, and short reaction time) and converts various thiols into the corresponding 1,3-butadiynyl sulfides. A cysteine-derived diynyl sulfide was further transformed into thiobitriazole and cyclobutene derivatives in good yields, underscoring the versatility of this approach. The substitution of an ethynyl group at the β-carbon of EBX enhances the reactivity of the EBX reagents. Further mechanistic and computational studies are currently ongoing in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included in the SI. Supplementary information: experimental details and characterization data, and copies of ¹H and ¹³C NMR spectra for selected compounds. See DOI: https://doi.org/10.1039/d5ob01384d.

Acknowledgements

We thank Prof. Kazuaki Fukushima (Hyogo Medical University) for his assistance with DFT calculation. This work was supported by JSPS KAKENHI Grant Numbers 19K06977 and 22K06530 and Grants for Research from SIS (The Society of Iodine Science), OGAWA Science and Technology Foundation, Takeda Science Foundation, Suzuken Memorial Foundation, and COMIT Collaborative Research 2023. We thank Enago (https://www.enago.jp) for the English language review.

References

1. L. B. Poole, Free Radicals Biol. Med., 2015, 80, 148–157.
2. P. Ochtrop and C. P. R. Hackenberger, Curr. Opin. Chem. Biol., 2020, 58, 28–36.
3. R. Frei and J. Waser, J. Am. Chem. Soc., 2013, 135, 9620–9623.
4. (a) E. M. D. Allouche, E. Grinhagena and J. Waser, Angew. Chem., Int. Ed., 2022, 61, e202112287; (b) R. Frei, M. D. Wodrich, D. P. Hari, P. A. Borin, C. Chauvier and J. Waser, J. Am. Chem. Soc., 2014, 136, 16563–16573; (c) D. Abegg, R. Frei, L. Cerato, D. P. Hari, C. Wang, J. Waser and A. Adibekian, Angew. Chem., Int. Ed., 2015, 54, 10852–10857; (d) M. D. Wodrich, P. Caramenti and J. Waser, Org. Lett., 2016, 18, 60–63; (e) R. Tessier, R. K. Nandi, B. G. Dwyer, D. Abegg, C. Sornay, J. Ceballos, S. Erb, S. Cianférani, A. Wagner, G. Chaubet, A. Adibekian and A. Waser, Angew. Chem., Int. Ed., 2020, 59, 10961–10970; (f) A. K. Mishra, R. Tessier, D. P. Hari and J. Waser, Angew. Chem., Int. Ed., 2021, 60, 17963–17968; (g) J. Ceballos, E. Grinhagena, G. Sangouard, C. Heinis and J. Waser, Angew. Chem., Int. Ed., 2021, 60, 9022–9031; (h) X. Liu, X. Ji, C. Heinis and J. Waser, Angew. Chem., Int. Ed., 2023, 62, e202306036.
5. For selected reviews for hypervalent iodine compounds: (a) B. Olofsson, I. Marek and Z. Rappoport, PATAI'S Chemistry of Functional Groups, Wiley, 2019, pp. 1032; (b) A. Yoshimura and V. V. Zhdankin, Chem. Rev., 2024, 124, 11108–11186.
6. For selected reviews for alkynyl benziodoxolones: (a) D. P. Hari, S. Nicolai and J. Waser, Alkynylations and Vinylations, Patai's Chemistry of Functional Groups, John Wiley & Sons, Ltd, 2018; (b) J. P. Brand and J. Waser, Chem. Soc. Rev., 2012, 41, 4165–4179.
7. C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165–195.
8. M. Ochiai and N. Tada, Chem. Commun., 2005, 5083–5085.
9. For selected reviews for hypervalent bromine compounds: (a) K. Miyamoto, Chemistry of Hypervalent Bromine, Patai's Chemistry of Functional Groups, John Wiley & Sons, Ltd, 2018; (b) B. Winterson, T. Patra and T. Wirth, Synthesis, 2022, 1261–1271.
10. (a) J. Taguchi, K. Tokunaga, H. Tabuchi, T. Nishiyama, I. Kii and T. Hosoya, Chem. Commun., 2024, 60, 14581–14584; (b) A. Yashiro, Y. Tanaka, T. Tada, S. Fujii, T. Nishino and M. Akita, Chem. – Eur. J., 2021, 27, 9666–9673; (c) M. P. Smela and T. R. Hoye, Org. Lett., 2018, 20, 5502–5505; (d) H. Yan, S. I. Lim, L. Zhang, S. Gao, D. Mott, Y. L. R. Loukrakpam, D. An and C. Zhong, J. Mater. Chem., 2011, 21, 1890–1901; (e) D. B. Werz, R. Gleiter and F. Rominger, Eur. J. Inorg. Chem., 2004, 4021–4027; (f) D. B. Werz, R. Gleiter and F. Rominger, J. Am. Chem. Soc., 2002, 124, 10638–11063; (g) H. Takeda, S. Shimada, A. Masaki, K. Hayamizu, H. Matsuda, F. Nakanishi, S. Okada and H. Nakanishi, Macromol. Chem. Phys., 1999, 200, 1240–1243.
11. (a) Q. Su, H. Yan, S. Gao, D. Xie, Q. Cai, G. Shao, Z. Peng and D. An, Synth. Commun., 2013, 43, 2648–2655; (b) Y. Zhang, J. Xiao, W. Dong, Z. Peng and D. An, Heteroat. Chem., 2015, 26, 449–454.
12. P. J. Stang and V. V. Zhdankin, J. Am. Chem. Soc., 1990, 112, 6437–6438.
13. (a) T. Kano, R. Uozumi, T. Maruyama, N. Tada and A. Itoh, J. Org. Chem., 2024, 89, 11761–11765; (b) R. Kawakami, S. Usui, N. Tada and A. Itoh, Chem. Commun., 2023, 59, 450–453; (c) A. Shimizu, A. Shibata, T. Kano, Y. Kumai, R. Kawakami, H. Esaki, K. Fukushima, N. Tada and A. Itoh, Org. Lett., 2022, 24, 8859–8863; (d) R. Takai, D. Shimbo, N. Tada and A. Itoh, J. Org. Chem., 2021, 86, 4699–4713; (e) D. Shimbo, T. Maruyama, N. Tada and A. Itoh, Org. Biomol. Chem., 2021, 19, 2442–2447; (f) T. Ura, D. Shimbo, M. Yudasaka, N. Tada and A. Itoh, Chem. – Asian J., 2020, 15, 4000–4004; (g) D. Shimbo, A. Shibata, M. Yudasaka, T. Maruyama, N. Tada, B. Uno and A. Itoh, Org. Lett., 2019, 21, 9769–9773; (h) M. Yudasaka, D. Shimbo, T. Maruyama, N. Tada and A. Itoh, Org. Lett., 2019, 21, 1098–1102.
14. For selected reviews: (a) A. L. K. S. Shun and R. R. Tykwinski, Angew. Chem., Int. Ed., 2006, 45, 1034–1057; (b) M. Gholami and R. R. Tykwinski, Chem. Rev., 2006, 106, 4997–5027.
15. N. Matsunaga, D. W. Rogers and A. A. Zavitsas, J. Org. Chem., 2003, 68, 3158–3172.
16. (a) A. Imamura and Y. Aoki, Int. J. Quantum Chem., 2012, 113, 423–427; (b) W. A. Chalifoux, R. McDonald, M. J. Ferguson and R. R. Tykwinski, Angew. Chem., Int. Ed., 2009, 48, 7915–7919.
17. We synthesized phenyl diynyl benziodoxolone (Ph-diyne-BX) using our synthetic method for TIPS-diyne-BX; however, we could not obtain the product in pure form owing to its instability during purification, recrystallization, and silica gel column chromatography.
18. P. Palamini, J. Borrel, M. Djaïd, M. Delattre and J. Waser, Org. Lett., 2023, 25, 7535–7539.
19. B. Liu, J. V. Alegre-Requena, R. S. Paton and G. M. Miyake, Chem. – Eur. J., 2020, 26, 2386–2394.
20. P. Destito, J. R. Couceiro, H. Faustino, F. López and J. L. Mascareñas, Angew. Chem., Int. Ed., 2017, 56, 10766–10770.
21. Deprotection of the TIPS group of 3m yielded unidentified products instead of the desired deprotected product.
22. N. Riddell and W. Tam, J. Org. Chem., 2006, 71, 1934–1937.

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