Triiodoisocyanuric acid: a new and convenient reagent for regioselective iodination of activated arenes

COMMUNICATION

Triiodoisocyanuric acid: a new and convenient reagent for regioselective iodination of activated arenes^#

Rodrigo da S. Ribeiro; Pierre M. Esteves^*; Marcio C. S. de Mattos^*

Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68545, 21945-970 Rio de Janeiro-RJ, Brazil

ABSTRACT

Triiodoisocyanuric acid (TICA) was prepared in 90% yield by heating trichloroisocyanuric acid with iodine in a sealed tube. The reaction of TICA with activated arenes in acetonitrile led to an efficient and highly regioselective formation of the corresponding iodoarenes, in 73-93% isolated yield. Aniline and phenol are monoiodinated regioselectively using MeOH (53%) and CH₂Cl₂ (88%) as solvents, respectively.

Keywords: triiodoisocianuric acid, iodination, activated aromatic compound, iodoarene, electrophilic halogenation

RESUMO

O ácido triiodo-isocianúrico (TICA) foi preparado em 90% de rendimento a partir do aquecimento do ácido tricloro-isocianúrico com iodo em um tubo selado. A reação do TICA com arenos ativados em acetonitrila gera regiosseletivamente os respectivos iodo-arenos em 73-93% de rendimento isolado. Anilina e fenol também são monoiodados seletivamente usando MeOH (53%) e CH₂Cl₂ (88%) como solventes, respectivamente.

Introduction

Iodoarenes are valuable, versatile synthetic intermediates and have found wide applications in pharmacology, medicine and biochemistry.¹ Introduction of an iodine atom into organic molecules is frequently an important step in organic synthesis since the iodine atom can easily be replaced by another group in a nucleophilic, free radical substitution or transition metal catalyzed condensation, as for example, Heck, Stille, Negishi and Buchwald cross-coupling reactions to produce new C–;C, C–S, C–O and C–N bonds.² However, the low electrophilic nature of the molecular iodine, compared to the molecular bromine and chlorine, difficults direct iodination.³ The direct iodination is also hampered by the formation of HI, which can cause protolytic cleavage of sensitive compounds.⁴ Hence many different synthetic methods (direct and indirect), or their improvements, have been reported for effective preparation of iodoarenes.¹

Iodination of activated aromatic compounds was carried out by using molecular iodine or iodide ions together with an oxidizing agent, such as nitrogen dioxide,⁵ tetrabutylammonium peroxydisulfate,⁵ air/bismuth salts,⁷ SiO₂–Fe(NO₃)₃•9H₂O,⁸ hydrogen peroxide⁹ and diiodine pentoxide/H₂SO₄/HOAc¹⁰ in order to generate a better electrophile within the reaction. However, the oxidizing reagents can degrade sensitive groups present in the substrate. Other direct iodination methods have been recently developed using iodenium ("I⁺") donating systems, such as CF₃COOAg/I₂,¹¹ NIBTS/CF₃CO₂H,¹²N-Iodosaccharin,¹³ KICl₂,¹⁴ ICl/In(OTf)₃,⁴ IPy₂BF₄/ CF₃SO₃H,¹⁵ NIS/CF₃CO₂H,¹⁶ NaOCl/NaI,¹⁷ iodine/CAN,¹⁸ NH₄I/oxone¹⁹ and NaIO₄/KI/NaCl.²⁰ However, most of these methods require hazardous or toxic reagents or high reaction temperature for long reaction time.

N-Halocompounds are useful halogenating reagents in organic chemistry.²¹ Recent papers have demonstrated that trihaloisocyanuric acids (Figure 1), such as trichloroisocyanuric²² (TCCA), tribromoisocyanuric²³ (TBCA) and bromodichloroisocyanuric acids²⁴ are efficient halogenating agents of activated aromatic compounds, due to their capability of halenium ('X⁺') atoms transfer. These trihaloisocyanuric acids are also very interesting from the green chemistry point of view,²⁵ since they halogenate organic compounds without using toxic and corrosive X₂ and also present good atom economy.

Triiodoisocyanuric acid (TICA, Figure 1), an analogue of TCCA and TBCA synthesized by Gottardi more than 35 years ago,²⁶ was recently reported by us as an efficient coiodination reagent of alkenes with oxygenated nucleophiles.²⁷ This motivated us to use it in our studies of iodination of activated aromatic compounds. TICA has also the advantage of transferring three equivalents of iodine atom to the substrate, representing an atom economy of up to 75%.

In this work we describe a new methodology for the regiosselective iodination of activated aromatic rings using TICA as the source of I⁺.²⁸

Results and Discussion

TICA was prepared in 90% yield by heating for 24 h the readily available trichloroisocyanuric acid²⁹ with 3.3 mol equiv. of I₂ at 180 ºC followed by 48 h at 230 ºC in a sealed tube (Scheme 1).

The reaction of arenes with TICA (0.34 mol equiv.) in acetonitrile at room temperature gave after work-up the corresponding monoiodo arenes in good to excellent yields (Table 1). These reactions are very simple and of easy work up, giving pure products that need no further purification. The regioselectivity of the reactions was very high and no regioisomers were detected by the analytical procedures employed (HRGC and ¹H and ¹³C NMR spectroscopy). However an exception was observed in the reaction of toluene that produced both regioisomers o- and p-iodotoluene (Table 1, entry 10).

Highly activated arenes, such as aniline and phenol, were successfully monoiodinated by TICA in MeOH and CH₂Cl₂, respectively (Table 1, entries 8 and 9). On the other hand, non-activated arenes failed to undergo iodination under these conditions, e.g., benzene that gave no product after 72 hours of reaction (Table 1, entry 11). In weakly activated arene, as toluene, the reaction is slow but it is possible to observing the consumption of all substrate after 48 h with the use of a small excess TICA (Table 1, entry 10). Diiodination products can also be obtained by using 0.7 mol equiv. of TICA (Table 1, entry 7).

Experimental

Procedure for preparation of TICA

Iodine (184.6 mmol, 46.85 g) and trichloroisocyanuric acid (55.93 mmol, 13.00 g) were added to a 100 cm³ sealed tube and heated in a sand bath at 180 ºC. After 24 h, the ICl produced was distilled off under reduced pressure and the sealed tube was heated again at 230 ºC during 48 h. Evaporation of ICl under reduced pressure and heating gave triiodoisocyanuric acid as a brown solid in 90% yield.³⁰ mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3211, 3053, 2884, 2830, 2780, 1700, 1665, 1459, 1372, 1145, 1061, 1051, 732, 663, 533.

General procedure for iodination of activated arenes with TICA

To a stirred solution of the arene (2 mmol) in acetonitrile (MeOH in the case of aniline or CH₂Cl₂ in the case of phenol) (5 cm³), was added TICA (0.67 mmol) at room temperature and in the absence of light. The reaction was monitored by HRGC-MS and after the specified time showed in Table 1, CH₂Cl₂ (10 cm³) was added, cyanuric acid was filtered off and the resulting solution was treated with 10% aq. NaHSO₃ (60 cm³). The aqueous phase was extracted with CH₂Cl₂ (2 × 10 cm³), the combined organic extract was washed with H₂O (60 cm³), dried (anhydrous Na₂SO₄) and filtered. The solvent was evaporated on a rotatory evaporator to give the pure product. Selected analytical data:

4-Iodo-anisol

¹H NMR (200 MHz, CDCl₃): δ 3.79 (s, 3H), 6.69 (d, J 8.8 Hz, 2H), 7.57 (d, J 8.8 Hz, 2H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 55.4, 82.8, 116.5, 138.3, 159.6 ppm.

2-Iodo-1,4-dimethoxybenzene

¹³C NMR (50 MHz, CDCl₃): δ 56.0, 57.1, 86.1, 111.7, 114.8, 124.9, 152.8, 154.4 ppm. MS: m/z 264 (M⁺, 100%), 249, 233, 221, 127, 122, 107, 92, 79, 77, 63.

1-Iodo-2-methoxynaphthalene

¹H NMR (200 MHz, CDCl₃): δ 4.03 (s, 3H), 7.21 (d, J 9.0 Hz, 1H), 7.40 (t, J 7.5 Hz, 1H), 7.56 (t, J 7.6 Hz, 1H), 7.76 (d, J 8.0 Hz, 1H), 7.83 (d, J 9.0 Hz, 1H), 8.17 (d, J 8.5 Hz, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 57.3, 87.8, 113.0, 124.4, 128.2, 128.3, 130.0, 130.4, 131.3, 135.7, 156.7 ppm.

2-Ethoxy-1-iodonaphthalene

¹H NMR (200 MHz, CDCl₃): δ 1.55 (t, J 7.0 Hz, 3H), 4.26 (q, J 7.0, 2H), 7.18 (d, J 9.0 Hz, 1H), 7.39 (t, J 7.4 Hz, 1H), 7.56 (t, J 7.5 Hz, 1H), 7.75 (d, J 9.9 Hz, 1H), 7.80 (d, J 9.0 Hz, 1H), 8.17 (d, J 8.5 Hz, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 15.2, 66.2, 89.0, 114.6, 124.4, 128.1, 128.2, 130.0, 130.3, 131.4, 135.8, 156.3 ppm.

4-Iodoacetanilide

mp 184 ºC (lit: 184 ºC)³¹ MS: m/z 261 (M⁺), 245, 219 (100%), 203, 127, 105, 92, 91, 76, 65, 43.

3-Iodo-1,2,4,5-tetramethylbenzene

¹H NMR (200 MHz, CDCl₃): δ 2.34 (s, 6H), 2.47 (s, 6H), 6.92 (s, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 21.7, 26.7, 111.6, 131.5, 134.2, 137.7 ppm.

1,4-Diiodo-2,3,5,6-tetramethylbenzene

¹H NMR (200 MHz, CDCl₃): δ 2.65 (s, 12H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 29.9, 112.3, 138.0 ppm.

4-Iodoaniline

mp 63 ºC (lit: 64-65 ºC)³² IR (KBr) ν_max/cm^-1: 3406, 3299, 3200, 3058, 3028, 1629, 1582, 1482, 1275, 815. MS: m/z 220 (M⁺ +1), 219 (M⁺, 100%), 191, 127, 109, 92, 65, 63, 52.

4-Iodophenol

mp 90-92 ºC (lit: 91-93ºC)³³ MS: m/z 220 (M⁺, 100%), 191, 127, 110, 93, 75, 65.

2-Iodotoluene

¹³C NMR (50 MHz, CDCl₃): δ 28.2, 101.3, 127.5, 128.2, 129.8, 139.0, 141.4 ppm. MS: m/z 218 (M⁺), 127, 91 (100%), 65, 51.

4-Iodotoluene

¹³C NMR (50 MHz, CDCl₃): δ 21.1, 90.3, 131.3, 137.3, 137.5 ppm. MS: m/z 218 (M⁺), 127, 91 (100%), 65, 51.

Conclusions

In conclusion, we have developed a very simple, efficient and ecofriendly methodology for the regioselective iodination of activated aromatic rings in good to excellent yields under mild conditions. Furthermore, the reagent is very safe, easily handled and more useful in terms of atom economy than the traditional reagents used in iodination reactions.

Acknowledgments

The authors thank CNPq, CAPES, and FAPERJ for the financial support.

References

1. Stavber, S.; Jereb, M.; Zupan, M.; Synthesis 2008, 1487; Seevers, R. H.; Counsell, R. E.; Chem. Rev. 1982, 82, 575; Merkushev, E. B.; Synthesis 1988, 923; Larock, R. C.; Lee, N. H.; J. Org. Chem. 1991, 56, 6253; Swenton, J. S.; Callinan, A.; Wang, S.; J. Org. Chem. 1992, 57, 78; Negishi, E.; Copéret, C.; Ma, S.; Liou, S.-Y.; Liu, F.; Chem. Rev. 1996, 96, 365; Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S.; J. Org. Chem. 1993, 58, 3194.

2. Sonesson, C.; Larhed, M.; Nyqvist, C.; Hallberg, A.; J. Org. Chem. 1996, 61, 4756; Liron, F.; Gervais, M.; Peyrat, J. -F.; Alami, M.; Brion, J. -D.; Tetrahedron Lett. 2003, 44, 2789; Lin, W.; Ilgen, F.; Knochel, P.; Tetrahedron Lett. 2006, 47, 1941; Kwong, F. Y.; Buchwald, S. L.; Org. Lett. 2002, 4, 3517; Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L.; Org. Lett. 2002, 4, 973; Kwong, F. Y; Klapars, A.; Buchwald, S. L.; Org. Lett. 2002, 4, 581; Klapars, A.; Huang, X.; Buchwald, S. L.; J. Am. Chem. Soc. 2002, 124, 7421; Antilla, J. C.; Klapars, A.; Buchwald, S. L.; J. Am. Chem. Soc. 2002, 124, 11684; Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.; J. Am. Chem. Soc. 2001, 123, 7727.

3. Mukaiyama, T.; Kitagawa, H.; Matsuo, J. -I.; Tetrahedron Lett. 2000, 41, 9383.

4. Johnsson, R.; Meijer, A.; Ellervik, U.; Tetrahedron 2005, 61, 11657.

5. Noda, Y.; Kashima, M.; Tetrahedron Lett. 1997, 38, 6225.

6. Yang, S. G.; Kim,Y. H.; Tetrahedron Lett. 1999, 40, 6051.

7. Wan, S.; Wang, S. R.; Lu, W.; J. Org. Chem. 2006, 71, 4349.

8. Tilve, R. D.; Alexander, V. M.; Khadilkar, B. M.; Tetrahedron Lett. 2002, 43, 9457.

9. Narender, N.; Reddy, K. S. K; Mohan, K. V. V. K.; Kulkarni. S. J.; Tetrahedron Lett. 2007, 48, 6124.

10. Brazdil, L. C.; Cutler, C. J.; J. Org. Chem. 1996, 61, 9621.

11. Henne, A. L.; Zimmer, W. F.; J. Am. Chem. Soc. 1951, 73, 1362.

12. Ghorbani-Vaghei, R.; Tetrahedron Lett. 2003, 44, 7529.

13. Dolenc, D.; Synlett 2000, 544.

14. Garden, S. J.; Torres, J. C; Melo, S. C. de S.; Lima, A. S.; Pinto, A. C.; Lima, E. L. S;. Tetrahedron Lett. 2001, 42, 2089.

15. Barluenga, J.; Gonzalez, J. M.; Garcia-Martin, M. A.; Campos, P. J.; Asensio, G.; J. Org. Chem. 1993, 58, 2058.

16. Castanet, A. -S.; Colobert, F.; Broutin, P. -E.; Tetrahedron Lett. 2002, 43, 5047.

17. Edgar, K. J.; Falling, S. N.; J. Org. Chem. 1990, 55, 5287.

18. Das, B.; Krishnaiah, M.; Venkateswarlu, K.; Reddy, V. S.; Tetrahedron Lett. 2007, 48, 81.

19. Mohan, K. V. V. K.; Narender, N.; Kulkarni, S. J.; Tetrahedron Lett. 2004, 45, 8015.

20. Emmanuvel, L.; Shukla, R. K.; Sudalai, A.; Gurunath, S.; Sivaram, S.; Tetrahedron Lett. 2006, 47, 4793.

21. Kolvani, E.; Ghorbani-Choghamarani, A.; Salehi, P.; Shirini, F.; Zolfigol, M. A.; J. Iran. Chem. Soc. 2007, 4, 126. ; de Souza, S. P. L.; da Silva, J. F. M.; de Mattos, M. C. S.; Quim. Nova 2006, 29, 1061.

22. Mendonça, G. F.; de Mattos, M. C. S.; Quim. Nova 2008, 31, 798; Mendonça, G. F; Magalhães, R. R; de Mattos, M. C. S.; Esteves, P. M.; J. Braz. Chem. Soc. 2005, 16, 695.

23. de Almeida, L. S; Esteves, P. M.; de Mattos, M. C. S.; Synthesis 2006, 221.

24. de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S.; Synlett 2007, 1687.

25. Sanseverino, A. M.; Quim. Nova 2000, 23, 102.

26. Gottardi, W.; Monatsh. Chem. 1970, 101, 655.

27. Ribeiro, R. da S.; Esteves, P. M.;. de Mattos, M. C. S.; Tetrahedron Lett. 2007, 48, 8747.

28. For our works on the utilization of trihaloisocyanuric acids in organic reactions see: de Souza, A. V. A.; Mendonça, G. F.; Bernini, R. B.; de Mattos, M. C. S.; J. Braz. Chem. Soc. 2007, 18, 1575; Tozetti, S. D. F.; de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S.; J. Braz. Chem. Soc. 2007, 18, 675; de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S. Synlett 2006, 1515; Mendonça, G. F.; Sanseverino, A. M.; de Mattos, M. C. S. Synthesis 2003, 45; Wengert, M.; Sanseverino, A. M.; de Mattos, M. C. S.; J. Braz. Chem. Soc. 2002, 13, 700.

29. Tilstam, U.; Weinmann, H.; Org. Process Res. Dev. 2002, 6, 384; Barros, J. C.; Synlett 2005, 2115.

30. At room temperature TICA decomposes slowly with formation of I₂. On the other hand, in the presence of light the decomposition is very fast. However, if stored in dark in a freezer, TICA proved to be stable for at least one year.

31. Felix, G.; Dunoguès, J.; Calas, R.; Angew. Chem., Int. Ed. 1979, 91, 430.

32. Chretien, J.–M.; Zammattio, F.; Le Grognel, E.; Paris, M.; Cahingt, B.; Montavon, G.; Quintard, J.–P.; J. Org. Chem. 2005, 70, 2870.

33. Yasuhara, A.; Kasano, A.; Sakamoto, T.; J. Org. Chem. 1999, 64, 4211.

Received: February 26, 2008

Web Release Date: August 5, 2008

#

Dedicated to Prof. W. Bruce Kover on the occasion of his 70th anniversary and retirement.

Publication Dates

• Publication in this collection
  03 Oct 2008
• Date of issue
  2008

History

• Accepted
  05 Aug 2008
• Received
  26 Feb 2008