Efficient synthesis of 1-iodoalkynes via Al₂O₃ mediated reaction of terminal alkynes and N-iodosuccinimide

Abstract

Iodination of terminal alkynes using N-iodosuccinimide (NIS) in the presence of γ-Al₂O₃ was developed to afford 1-iodoalkynes with good to excellent yields (up to 99%). This described approach featured excellent chemoselectivity, good functional group tolerance, and utilization of an inexpensive catalyst.

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1-Iodoalkynes are both highly versatile synthons in organic synthesis and valuable building blocks in materials and polymer sciences.^1,2 Traditional procedures for generating 1-iodoalkynes include iodination of metal acetylides (Scheme 1, path a),³ direct iodination of terminal alkynes (path b),⁴ iodination of propiolic acid/trialkylsilylacetylides (path c),^5,6 and a two-step homologation/iodination or elimination sequence from aldehydes or benzylic bromides (path d).^7,8 Among these achievements, path b, the preparation of 1-iodoalkynes from terminal alkynes, is highly desirable. In this regard, various iodinating conditions, including nBuLi/I₂,^4a EtMgBr/I₂,^4b I₂/DMAP,^4c NIS/AgNO₃,^4d NIS/BnN₃,^4e NIS/DBU,^4f NIS/Ag/C₃N₄,^4g KI/CuI/PhI(OAc)₂/Et₃N,^4h Me₃SiI/PhI(OAc)₂,⁴ⁱ CuI/TBAB/Et₃N,^4j TBAI/Oxone,^4k KI/TBHP,^4l TBAI/PhI(OAc)₂,^4m chloramine-B/KI,⁴ⁿ KI/Cu₂SO₄/BPDS,^4o ZnI₂/TBN,^4p NIS/[Au(AIPr)(NEt₃)][HF₂],^4q HMBMIBDCI/DBU,^4r NaI/MeOH/divided cell,^4s and N-iodomorphonine/CuI,^4t have been reported. However, some of these approaches might suffer from expensive metal catalysts, hazardous or toxic reagents, harsh reaction conditions, or generation of wastes that bring about environmental problems, thereby restricting their practical applications. Though considerable progress has been achieved, the development of efficient and environmentally benign protocols is still required.

Scheme 1 Approaches towards to 1-iodoalkynes.

It is well recognized that solids can play a vital role in developing new cleaner technologies via their capacities to serve as catalysts or support reagents and influence product selectivity, and some books have documented the applications of solids in organic synthesis.^9–11 Aluminum oxide (Al₂O₃) is an inert, odorless and white amorphous material, and has been used as catalyst in various industrial processes for many years.^12,13 But the utilization of aluminum oxide in synthetic organic chemistry especially for halogenation of aromatic compounds and alkynes is very little.^14–18 γ-Aluminum oxide is one of the three common crystal forms of aluminum oxide. Pagni and Kabalka described γ-Al₂O₃ mediated iodination of alkynes and aromatic substrates with I₂ to afford E-diiodoalkenes and iodinated aromatic compounds, respectively.¹⁴ Those iodinations did not occur without the activation of γ-Al₂O₃.

N-Iodosuccinimide (NIS) is a well-known iodinating agent and widely used in organic synthesis. Iodination with N-iodosuccinimide (NIS) often needs activating reagents. However, any accompanying reagents used along with iodinating reagents should be easily available to exploit more simple and efficient iodination procedure. Inspired by the indispensable role of γ-Al₂O₃ in the iodination of alkynes and aromatic compounds,¹⁴ we envisioned that γ-Al₂O₃ could activate the N-iodosuccinimide to generate 1-iodoalkynes from terminal alkynes. Herein, we report the γ-Al₂O₃ mediated direct iodination of terminal alkynes for the synthesis of 1-iodoalkynes under mild reaction condition.

As shown in Table 1, the initial experiment was carried out by adding N-iodosuccinimide (NIS) 2a (2.2 mmol) to a solution of phenyl acetylene 1aa (2.0 mmol) and neutral γ-Al₂O₃ (2.6 mmol) in CH₃CN. Surprisingly, the reaction afforded the desired product 1-(iodoethynyl)benzene 3aa in 90% yield after stirred at 80 °C for 1 h (Table 1, entry 1). To our delight, the reaction could provide 98% yield with the aid of 4 Å MS (entry 2). At the same time, the product 3aa could be obtained in 95% yield without the help of 4 Å MS when the amount of CH₃CN used in the reaction was reduced from 10 mL to 2 mL (entry 2). Markedly, we obtained a mixture of 1aa, 3aa, 1,2-diiodovinylbenzene 4 and 2,2-diiodo-1-phenylethanone 5 in the absent of 4 Å MS and Al₂O₃ (entry 3). In addition, the 3aa was obtained in 41% yield only in the presence of 4 Å MS (entry 3). Therefore, the Al₂O₃ was indispensable to this iodination reaction (Table S1†). Similarly, high yields of 1-iodoalkyne 3aa were also obtained when basic and acidic Al₂O₃ were used instead of neutral Al₂O₃ (entry 4–5). Hence, the reaction was further examined in the presence of neutral Al₂O₃. The effort to decrease the reaction temperature to 25 °C only led to low yield (entry 6). Subsequently, we probed different solvents including DMF, THF, EA, MeOH and hexane, but those solvents resulted in poor yields of desired product (entry 7–11). Moreover, the reaction was investigated by varying the amount of Al₂O₃ and NIS to enhance the performance of the reaction (Table 1, entry 12–15). With 1.0 equivalents of NIS, the reaction generated 81% yield of 1-iodoalkyne 3aa (entry 12). However, when higher or lower amount of Al₂O₃ was used, low yields of the desired product were observed (entry 13–15). Finally, the best conditions to obtain the 1-iodoalkyne 3aa were treatment of 1aa with 1.1 equivalents of NIS, 1.3 equivalents of neutral γ-Al₂O₃ and 4 Å MS in CH₃CN at 80 °C for 1 h. With the optimized conditions in hand, we also studied the halogenation of phenyl acetylene 1aa and used various halogenated reagents, including N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide and N-chlorosuccinimide. These attempts did not provide satisfied results (Scheme S1†).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	2a (equiv.)	T (°C)	Al2O3 (equiv.)	Yield^b (%)
a Unless noted otherwise, all reaction were conducted using phenylacetylene 1aa (2.0 mmol), N-iodosuccinimide 2a (2.2 mmol), 200 mg 4 Å MS, 265.0 mg neutral Al2O3 in 10 mL CH3CN at 80 °C for 1 h.b Isolated yield.c No 4 Å MS.d No Al2O3 and 4 Å MS, HPLC analysis of the reaction mixture after reacting at 80 °C for 1 h showed the molar ratio of 1aa to 1-iodoalkyne 3aa to 1,2-diiodovinylbenzene 4 to 2,2-diiodo-1-phenylethanone 5 was 8 : 23 24 45.e No Al2O3.f Basic Al2O3 was used.g Acidic Al2O3 was used.h The reaction was conducted in 2 mL CH3CN. EA = ethyl acetate.
1	CH3CN	1.1	80	1.3	90^c
2	CH3CN	1.1	80	1.3	98(95^h)
3	CH3CN	1.1	80	—	—^d(41^e)
4	CH3CN	1.1	80	1.3^f	96
5	CH3CN	1.1	80	1.3^g	97
6	CH3CN	1.1	25	1.3	42
7	DMF	1.1	80	1.3	63
8	THF	1.1	80	1.3	78
9	EA	1.1	80	1.3	86
10	MeOH	1.1	80	1.3	79
11	Hexane	1.1	80	1.3	62
12	CH3CN	1.0	80	1.3	81
13	CH3CN	1.1	80	1.0	84
14	CH3CN	1.1	80	0.1	70
15	CH3CN	1.1	80	2.0	91

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Based on the optimized reaction conditions, the generality of the direct iodination of various terminal alkynes was investigated (Table 2). Firstly, a wide variety of aromatic alkynes were firstly evaluated and could react with NIS to afford the corresponding 1-iodoalkynes 3ab–3au with good to excellent yields. Substrates having both electron-donating (e.g. Me, OMe, CH₂CN) and electron-withdrawing (e.g. Cl, Br, CF₃, CO₂Me, CN) groups were effectively furnished the desired products. The halogen substituted aromatic alkynes gave the respective 1-iodoalkynes 3ab–3aj in excellent yields in relation to the position of the halogen on the phenyl ring and the electronegativity of the halogen. Among them, the meta bromo substituted alkyne 1ai gave the best yield (99%). The para substituted aromatic alkynes 1ak–1ap afforded the corresponding products 3ak–3ap in good to excellent yields. Although the para formyl substituted alkyne 1am yielded the 1-iodoalkyne 3am in 82% yield, the alkyne 1al could provide the corresponding product in 99% yield. Notably, the para cyanomethyl substituted alkyne 1ap afforded the desired product in almost quantitative yield (>99%). The dimethoxy substituted alkyne 1at provided better yield than the single methoxy substituted alkynes (1aq–1as). The 1,4-diethynylbenzene 1au could also be iodinated to generate the desired bisiodinated product in 99% yield. Secondly, the hetero aromatic and aliphatic alkynes were examined under the optimized conditions. The hetero aromatic alkynes delivered the iodination products 3av, 3aw and 3ax in 88%, 93% and 91% yield, respectively. The iodination reaction of aliphatic alkynes underwent smoothly to afford the corresponding products 3ay–3bb in good yields. The conjugated enyne 1bc could also react with NIS and gave the anticipated product 3bc in 80% yield. In addition, the iodination of more reactive alkyne 1bd was also evaluated and gave the synthetically useful 3bd in 93% yield. Finally, we also chose five terminal alkynes (1ab, 1af, 1al, 1an, 1ar) to examine the direct iodination requiring a small amount of solvent. The yields of solvent-reduced reaction (values in parentheses) performed in 2 mL CH₃CN were comparable to the yields of the reaction conducted in 10 mL CH₃CN. These results further confirmed that the 4 Å MS was not essential for the Al₂O₃ mediated iodination (Table S1†).

Table 2 Scope of Al₂O₃/NIS mediated iodination^a

a Reaction conditions: 1 (2.0 mmol), 2a (2.2 mmol), 4 Å MS (200 mg), Al₂O₃ (2.6 mmol), CH₃CN (10 mL), 80 °C, 1 h. Isolated yields are given. The values in parentheses are the yields of reaction conducted in 2 mL CH₃CN in the absent of 4 Å MS.

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To further explore the potential of this protocol, we conducted the Al₂O₃ mediated direct iodination system for larger-scale synthesis (Scheme 2). The iodination reaction with (10 mmol, 1.0213 g) of phenylacetylene 1aa in 50 mL CH₃CN afforded 96% yield. Delightfully, when the reaction was performed in 4 mL CH₃CN, the yield could reach to 98% (value in parentheses). Moreover, the iodination of 1af, 1ak and 1ap proceeded smoothly in CH₃CN, producing the corresponding 1-iodoalkynes in 97%, 94% and 98% yield, respectively. Finally, the larger scale reaction of aliphatic alkyne 1bb, could also generate 3bb in 90% yield. These excellent results indicated the promise of this direct iodination system for larger-scale preparation of 1-iodoalkynes from terminal alkynes.

Scheme 2 A Scale-up synthesis of 1-iodoalkynes.

As presented in Scheme 3, we also tried to construct mono-, di-, and tri-iodination of terminal alkynes based on direct iodination mediated by γ-Al₂O₃ using phenyl acetylene 1aa as the model substrate. As depicted in the literature,^14b the di-iodination product 6 could be obtained in 97% yield after stirred at 80 °C for 2 h in the presence of I₂. Combining the NIS and I₂ system in one pot provided the corresponding tri-iodination product 7 in 94% yield.

Scheme 3 Al₂O₃ mediated chemoselective iodination of phenyl acetylene.

Finally, we studied the recyclability of Al₂O₃ and 4 Å MS. Al₂O₃ and 4 Å MS could be used as a recyclable catalyst for the direct iodination of phenyl acetylene 1aa (10 mmol) as it provided 96%, 93% and 88% yield at the first, second and third run, respectively (Fig. S1†). The severe decrease of the yield of the iodination was probably because the active sites of Al₂O₃ were blocked by unknown compounds and the unavoidable loss of solid catalyst during recovery and washing.

Although the detailed mechanism for the γ-Al₂O₃ mediated iodination remains unclear, we proposed that the dehydrated surface of γ-Al₂O₃, which contains partly exposed Al³⁺ and O²⁻, could serve as an effective medium for electrophilic iodination and greatly increase the chemoselectivity and rate of the reaction. Investigation of the detail mechanism and further applications of this methodology are toward in our laboratory.

Conclusions

In conclusion, we have developed an efficient approach for the synthesis of 1-iodoalkynes via γ-Al₂O₃ mediated direct iodination of terminal alkynes in the presence of NIS. Firstly, this protocol has excellent reactivity, high chemoselectivity and good functional group tolerance, and can be used for large-scale preparation of various 1-iodoalkynes. Secondly, with the aid of Al₂O₃ the mono-, di-, and tri-iodination products could be obtained in high yield. Thirdly, the Al₂O₃ and 4 Å MS could be reused for the direct iodination of terminal alkynes at least once without severe decrease of the yield.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the Hubei Provincial Department of Education (T201719) for generous financial support.

References

1. For reviews, see: (a) A. Haque, R. A. Al-Balushi, I. J. Al-Busaidi, M. S. Khan and P. R. Raithby, Chem. Rev., 2018, 118, 8474–8597; (b) W. Wu and H. Jiang, Acc. Chem. Res., 2014, 47, 82483–82504; (c) W. Shi and A. Lei, Tetrahedron Lett., 2014, 55, 2763–2772; (d) J. P. Brand and J. Waser, Chem. Soc. Rev., 2012, 41, 4165–4179.
2. For selected recent examples, see: (a) M. E. de Orbe, M. Zanini, O. Quinonero and A. M. Echavarren, ACS Catal., 2019, 9, 7817–7822; (b) X. Zeng, B. Chen, Z. Lu, G. B. Hammond and B. Xu, Org. Lett., 2019, 21, 2772–2776; (c) S. M. Khake, S. Jain, U. N. Patel, R. G. Gonnade, K. Vanka and B. Punji, Organometallics, 2018, 37, 2037–2045; (d) X. Zeng, S. Liu, G. B. Hammond and B. Xu, ACS Catal., 2018, 8, 904–909; (e) G. Jiang, J. Li, C. Zhu, W. Wu and H. Jiang, Org. Lett., 2017, 19, 4440–4443; (f) R. Chung, A. Vo and J. E. Hein, ACS Catal., 2017, 7, 2505–2510; (g) P. J. Gonzalez-Liste, J. Francos, S. E. Garcia-Garrido and V. Cadierno, J. Org. Chem., 2017, 82, 1507–1516; (h) X. Zeng, S. Liu, Z. Shi and B. Xu, Org. Lett., 2016, 18, 4770–4773; (i) L. Huang, A. M. Olivares and D. J. Weix, Angew. Chem., Int. Ed., 2017, 56, 11901–11905; (j) G. Jiang, C. Zhu, J. Li, W. Wu and H. Jiang, Adv. Synth. Catal., 2017, 359, 1208–1212; (k) J. Li, W. Hu, C. Li, S. Yang, W. Wu and H. Jiang, Org. Chem. Front., 2017, 4, 373–376; (l) M. Ramanathan and S. Liu, Tetrahedron, 2017, 73, 4317–4322; (m) V. K. Singh, A. Upadhyay and R. K. P. Singh, Tetrahedron Lett., 2017, 58, 156–158; (n) P. Szuroczki, B. Boros and L. Kollar, Tetrahedron, 2018, 74, 6129–6136; (o) M. Ye, Y. Wen, H. Li, Y. Fu and Q. Wang, Tetrahedron Lett., 2016, 57, 4983–4986; (p) C. R. Reddy, S. A. Panda and A. Ramaraju, J. Org. Chem., 2017, 82, 944–949; (q) R. M. Chowdhury and J. D. Wilden, Org. Biomol. Chem., 2015, 13, 5859–5861; (r) S. Mader, L. Molinari, M. Rudolph, F. Rominger and S. K. Hashmi, Chem.–Eur. J., 2015, 21, 3910–3913.
3. (a) G. W. Kabalka and A. R. Mereddy, Tetrahedron, 2004, 45, 1417–1419; (b) J. E. Luithle and J. Pietruszka, Eur. J. Org. Chem., 2000, 2557–2562; (c) I. J. Blackmore, A. N. Boa, E. J. Murray, M. Dennis and S. Woodward, Tetrahedron Lett., 1999, 40, 6671–6672; (d) T. Mandai, T. Matsumoto, M. Kawada and J. Tsuji, J. Org. Chem., 1992, 57, 6090–6094.
4. (a) D. L. Uasnov and H. Yamamoto, J. Am. Chem. Soc., 2011, 133, 1286–1289; (b) M. L. N. Rao and M. Periasamy, Synth. Commun., 1995, 25, 2295–2299; (c) L. Meng, P. Cai, Q. Guo and S. Xue, Synth. Commun., 2008, 38, 225–231; (d) S. Mader, L. Molinari, M. Rudolph, F. Rominger and S. K. Hashmi, Chem.–Eur. J., 2015, 21, 3910–3913; (e) B. Wang, J. Zhang, X. Wang, N. Liu, W. Chen and Y. Hu, J. Org. Chem., 2013, 78, 10519–10523; (f) M. Li, Y. Li, B. Zhao, F. Liang and L. Jin, RSC Adv., 2014, 4, 30046–30049; (g) W. Shi, Z. Guan, P. Cai and H. Chen, J. Catal., 2017, 353, 199–204; (h) J. Yan, J. Li and D. Cheng, Synlett, 2007, 2442–2444; (i) D. S. Rao, T. R. Reddy and S. Kashyap, Org. Biomol. Chem., 2018, 16, 1508–1518; (j) S. Chen, T. Hung, T. Lin and F. Tsai, J. Chin. Chem. Soc., 2009, 56, 1078–1081; (k) S. Kodumuri, S. Peraka, N. Mameda, D. Chevella, R. Banothu, K. S. Gajula, S. Thokali and N. Nama, ChemistrySelect, 2017, 2, 748–752; (l) K. R. Reddy, M. Venkateshwar, C. U. Maheswari and P. S. Kumar, Tetrahedron Lett., 2010, 51, 2170–2173; (m) Y. Liu, D. Huang, J. Huang and K. Maruoka, J. Org. Chem., 2017, 82, 11865–11871; (n) X. Liu, G. Chen, C. Li and P. Liu, Synlett, 2018, 2051–2055; (o) T. Ferris, L. Carroll, R. C. Mease, A. C. Spivey and E. O. Aboagye, Tetrahedron Lett., 2019, 60, 936–939; (p) S. Chen, X. Zhang, H. Zhao, X. Guo and X. Hu, Chin. J. Inorg. Chem., 2018, 38, 1172–1176; (q) A. Gomez-Herrera, F. Nahra, M. Brill, S. P. Nolan and C. S. J. Cazin, ChemCatChem, 2016, 8, 3381–3388; (r) M. Nouzarian, R. Hosseinzadeh and H. Golchoubian, Synth. Commun., 2013, 43, 2913–2925; (s) I. Nishiguchi, O. Kanbe, K. Itoh and H. Maekawa, Synlett, 2000, 89–91; (t) J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless and V. V. Fokin, Angew. Chem., Int. Ed., 2009, 48, 8018–8021.
5. (a) T. Nishikawa, S. Shibuya, S. Hosokawa and M. Isobe, Synlett, 1994, 485–486; (b) P. Starkov, F. Rota, J. M. D'Oyley and T. D. Sheppard, Adv. Synth. Catal., 2012, 354, 3217–3224.
6. (a) J. P. Das and S. Roy, J. Org. Chem., 2002, 67, 7861–7864; (b) D. Naskar and S. Roy, J. Org. Chem., 1999, 64, 4896–6897.
7. G. Pelletier, S. Lie, J. J. Mousseau and A. B. Charette, Org. Lett., 2012, 14, 5464–5467.
8. (a) Z. Wang, S. Campagna, K. Yang, G. Xu, M. E. Pierce, J. M. Fortunak and P. N. Confalone, J. Org. Chem., 2000, 65, 1889–1891; (b) P. Michel and A. Rassat, Tetrahedron Lett., 1999, 40, 8579–8581; (c) G. J. Hollingworth, A. M. E. Richecoeur and J. Sweeney, J. Chem. Soc., Perkin Trans. 1, 1996, 2833–2836; (d) G. J. Hollingworth and J. Sweeney, Synlett, 1993, 463–465; (e) B. Bonnet, Y. Le Gallic, G. Ple and L. Duhamel, Synthesis, 1993, 1071–1073; (f) E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 13, 3769–3772.
9. K. Smith, Solids Supports and Catalysts in Organic Synthesis, Ellis Horwood, Chichester, UK, 1992.
10. P. Laszlo, Preparative Chemistry Using Supported Reagents, Academic Press, London, UK, 1987.
11. H. van Bekkum, E. M. Flanigen and J. C. Jansen, Introduction to Zeolite Science and Practice, Studies in Surface Science and Catalysis, 1991, vol. 58.
12. H. Pines and W. O. Haag, J. Am. Chem. Soc., 1960, 82, 2471–2483.
13. A. Corado, A. Kiss, H. Knozinger and H. D. Muller, J. Catal., 1975, 37, 68–80.
14. (a) R. Boothe, C. Dial, R. Conaway, R. M. Pagni and G. W. Kabalka, Tetrahedron Lett., 1986, 27, 2207–2210; (b) S. Larson, T. Luidhardt, G. W. Kabalka and R. M. Pagni, Tetrahedron Lett., 1988, 29, 35–36; (c) G. Hondrogiannis, L. C. Lee, G. W. Abalka and R. M. Pagni, Tetrahedron Lett., 1989, 30, 2069–2070.
15. W. D. Bancroft and A. B. George, J. Phys. Chem., 1931, 35, 2943–2949.
16. W. S. Brey and K. A. Krieger, J. Am. Chem. Soc., 1949, 71, 3637–3641.
17. (a) M. Kodomari, N. Amanokura, K. Takeuchi and S. Yoshitomi, Bull. Chem. Soc. Jpn., 1992, 65, 306–308; (b) M. Kodomari, H. Satoh and S. Yoshitomi, J. Org. Chem., 1988, 53, 2093–2094; (c) M. Kodomari, H. Satoh and S. Yoshitomi, Ind. Chem. Libr., 1995, 7, 17–28.
18. S. Stavber, M. Jereb and M. Zupan, Synthesis, 2008, 1487–1513.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra00251h

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