Pyridinium Iodochloride: an Efficient Reagent for Iodination of Hydroxylated Aromatic Ketones and Aldehydes

Journal of the Chinese Chemical Society, 2008, 55, 871-874 871

Pyridinium Iodochloride: An Efficient Reagent for Iodination of Hydroxylated Aromatic Ketones and Aldehydes

Sandeep V. Khansole, Shyam S. Mokle, Mudassar A. Sayyed and Yeshwant B. Vibhute* P.G. Department of Chemistry, Yeshwant Mahavidyalaya, Nanded 431 602, (MS) India

Direct iodination of several reactive aromatic compounds like hydroxy substituted acetophenones and aldehydes with pyridinium iodochloride (PyICl) proceeded smoothly to afford the corresponding aromatic iodides in good to excellent yield. Pyridinium iodochloride has been found to be an efficient solid iodinating reagent with no hazardous effect and it can be handled safely.

Keywords: Iodination; Aromatic acetophenones; Aromatic aldehydes; Pyridinium iodochloride.

18 INTRODUCTION nium tetrafluoroborate (IPy2BF4), but in these reactions

The iodination of aromatic carbonyl compounds has HBF4 as the acid is required to liberate the iodinating agent been the subject of numerous studies due to the potential of and neutralize pyridine; to improve the yield of product the products to serve as intermediates in organic synthesis slightly an excess amount of reagent was required. Re- and to act as bacterial and fungicidal agents.1 Aromatic io- cently in our previous communication, iodination of aro- dides have long been used in organic synthesis as versatile matic compounds was demonstrated using iodine and iodic intermediates that can be transformed into a variety of func- acid as an iodinating agent.19,20 tional groups.2 They can be easily functionalized through Due to the poor electrophilic strength of iodine, direct metal catalyzed cross coupling reactions3 in the synthesis iodination of aromatic rings with iodine is difficult and re- of many interesting natural products4 and bioactive materi- quires the presence of an activating agent in order to pro- als.5 Iodoaromatic compounds are used in medicine as drug duce a strongly electrophilic I+ species. However some of or diagnostic aids, contrastors6 and radioactively labeled the existing methods have associated environmental haz- markers. They also have importance in medicinal and phar- ards with respect to handling and storage of molecular io- maceutical research.7 The chemistry dealing with selective dine, strongly acidic conditions, expensive and complex introduction of an iodine atom into an organic molecule has catalyst, toxic metallic compounds and rare oxidizing re- thus attracted broad interest in the wider scientific commu- agents that are difficult to prepare. Therefore there is a need nity. for a simple, less expensive and safer method for iodination Iodohydroxy aromatic ketones can be prepared by of hydroxy aromatic acetophenones and aldehydes. We re- Fries rearrangement8 of iodinated phenyl aromatic esters; port here iodination of several aromatic hydroxy aceto- however, after the Fries rearrangement, steam distillation is phenones and aldehydes by using pyridinium iodochloride required to separate the isomer which is a time consuming as iodinating agent. method and iodophenols are not easily available. In recent years, direct iodination methods have been RESULTS AND DISCUSSION intensively developed using iodinium donating systems, To illustrate the action of the proposed reagent we se- such as iodine-tetrabutylammonium peroxydisulfate,9 BuLi- lected several reactive aromatic substrates like hydroxy 10 11 CF3CH2I, iodine-nitrogen dioxide, iodine-F-TEDA- substituted acetophenones and aldehydes (Scheme I). The 12 13 14 BF4, iodine-iodine pentoxide, iodine monochloride, reaction was carried out by heating hydroxy ketones or al- 15 16 17 NIS-CF3SO3H, iodine-mercury salts, and NaOCl-NaI. dehydes with pyridinium iodochloride on a water bath for 1 The iodination of some unsaturated compounds in the h using methanol as solvent (Table 1). presence of HBF4 was reported using bis(pyridine) iodo- The isolated product indicated a regioselective iodin-

* Corresponding author. Tel: +91-2462-236835; Fax: +91-2462-253726; E-mail: [email protected] 872 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 Khansole et al.

Scheme I mass spectra were recorded on a Jeol D-300 spectrometer at 70 eV. The halogen (iodine) analysis was carried out in laboratory by the Parr bomb method. Preparation of pyridinium iodochloride To a solution of pyridine (7.9 g, 0.1 mole) in acetic acid, a solution of iodine monochloride (16 g, 0.1 mole) in acetic acid was added slowly at 0 °C with continuous stir- ring. The pale yellow solid obtained was filtered, dried and recrystallised by ethyl alcohol. The purity of reagent was ation had occured at the electron rich ortho or para posi- checked by thin layer chromatography. tion. When the ortho position was blocked, iodination only Typical procedure for iodination of hydroxylated aro- took place at the para position. Only nuclear iodination oc- matic ketones and aldehydes by pyridinium iodochloride curs and not at the side chain that is at –CH3 or –COCH3. 5-Bromo-2-hydroxy acetophenone (0.22 g, 1 mmol) CONCLUSION and pyridinium iodochloride (0.24 g, 1 mmol) were dis- In summary, a simple and convenient method for the solved in methanol (15 mL) and refluxed on a water bath iodination of hydroxylated aromatic acetophenones and al- for 2 h. The content was poured in ice cold water; the solid dehydes has been developed. The advantages include no that gets separated was filtered and recrystallised from catalyst, mild conditions, simple operation and short reac- ethyl alcohol. By using two equivalents of pyridinium iodo- tion time with excellent yield. Since the reagent is solid it chloride and one equivalent of substrate, diiodinated prod- can be easily weighed and has no hazardous effect. ucts were obtained.

EXPERIMENTAL SECTION SELECTED SPECTROSCOPIC DATA General procedures Melting points were determined in an open capillary 5-Bromo-2-hydroxy-3-iodoacetophenone -1 1 tube and are uncorrected. The purity of the compound has IR (cm ) umax: 1635 (C=O), 1580 (C=C). HNMR been checked by TLC. IR spectra were recorded in KBr on (CDCl3) d: 2.7 (s, 3H, COCH3), 7.82 (s, 1H, 4 Ar-H), 8.2 (s, 1 13 13 a Perkin Elmer spectrometer. HNMRand CNMRspec- 1H, 6 Ar-H), 12.85 (s, 1H, OH). CNMR(CDCl3) d: 24.2, tra were recorded in CDCl3 on a Varian Gemini 200 NMR 87.6, 115.2, 129.4, 131.2, 144.5, 167.3, 199.5; MS m/z + spectrometer using TMS as an internal standard. Elemental (M ) 340; Anal. calcd for C8H6BrIO2: C, 28.15; H, 1.75; X, analysis was carried out on a Carlo Erba 1108 analyzer. The 59.65. Found: C, 28.07; H, 1.62; X, 60.31.

Table 1. Iodination of hydroxylated aromatic acetophenones and aldehydes by pyridinium iodochloride M.P. °C Entry Substrate Product Yield (%) Found Lit. 1 2-Hydroxyacetophenone 2-Hydroxy-3,5-diiodoacetophenone 84 132 13221 2 4-Hydroxyaetophenone 4-Hydroxy-3,5-diiodoacetophenone 80 160 16222 3 5-Bromo-2-hydroxyacetophenone 5-Bromo-2-hydroxy-3-iodoacetophenone 85 104 10521 4 5-Chloro-2-hydroxyacetophenone 5-Chloro-2-hydroxy-3-iodoacetophenone 89 90 8921 5 2,4-Dihydroxyacetophenone 2,4-Dihydroxy-3,5-diiodoacetophenone 82 177 17823 6 5-Chloro-2-hydroxy-4-methylacetophenone 5-Chloro-2-hydroxy-3-iodo-4-methylacetophenone 80 79 7621 7 4-Hydroxy-3-methoxybenzaldehyde 4-Hydroxy-5-iodo-3-methoxybenzaldehyde 85 184 18524 8 2-Hydroxybenzaldehyde 2-Hydroxy-3,5-diiodobenzaldehyde 82 111 11025 9 4-Hydroxybenzaldehyde 4-Hydroxy-3,5-diiodobenzaldehyde 86 194 19526 10 5-Chloro-2-hydroxybenzaldehyde 5-Chloro-2-hydroxy-3-iodobenzaldehyde 79 77 7827 11 5-Bromo-2-hydroxybenzaldehyde 5-Bromo-2-hydroxy-3-iodobenzaldehyde 87 80 8127 12 2,4-Dihydroxybenzaldehyde 2,4-Dihydroxy-3,5-diiodobenzaldehyde 83 173 --- Iodination of Aromatic Ketones and Aldehydes J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 873

13 5-Chloro-2-hydroxy-3-iodoacetophenone 11.85 (s, 1H, OH). CNMR(CDCl3) d: 74.8, 81.1, 120.2, -1 1 + IR (cm ) umax: 1630 (C=O), 1570 (C=C). HNMR 141.3, 168.9, 184.4, 192.3; MS m/z (M ) 390; Anal. calcd

(CDCl3) d:2.75(s,3H,COCH3), 7.60 (s, 1H, 4 Ar-H), 7.83 for C7H4I2O3, C, 21.53; H, 1.02; I, 65.12. Found: C, 21.49; 13 (s, 1H, 6 Ar-H), 12.85 (s, 1H, OH). CNMR(CDCl3) d: H, 1.12; I, 65.19. 23.4, 86.7, 128.1, 129.1, 144.4, 164.4, 197. MS m/z (M+)

296.5; Anal. calcd for C8H6ClIO2: C, 32.37; H, 2.02; X, ACKNOWLEDGEMENTS 54.80. Found: C, 32.31; H, 2.11; X, 54.62. The authors are thankful to the principal Yeshwant Mahavidyalaya, Nanded, for providing laboratory facili- 2-4-Dihydroxy-3,5-diiodoacetophenone ties. The authors are also thankful to the Director of IICT, -1 1 IR (cm ) umax: 1640 (C=O), 1610 (C=C). HNMR Hyderabad, for providing spectral data and UGC New

(CDCl3) d:2.68(s,3H,COCH3), 8.68 (s 1H, 6 Ar-H), 8.35 Delhi, for providing research grant. 13 (s, 1H, OH), 11.82 (s, 1H, OH). CNMR(CDCl3) d: 23.9, + 73.6, 79.7, 121.9, 167, 182, 197.5; MS m/z (M ) 404; Anal. Received December 13, 2007. calcd for C8H6I2O3: C, 23.76; H, 1.48; X, 62.87. Found: C, 23.69; H, 1.71; X, 62.89. REFERENCES 1. Seevers, R. H.; Counsell, R. E. Chem. Rev. 1982, 82, 590. 5-Chloro-2-hydroxy-3-iodo-4-methylacetophenone 2. Farina, V. In Comprehensive Organometallic Chemistry II; -1 1 IR (cm ) umax: 1670 (C=O), 1570 (C=C). HNMR Abel, E. W.; Stone, F. G. A.; Wilkinson, G.; Ed.; Pergamon Press: Oxford, 1995; Vol. 12, pp 161-240. (CDCl3) d:2.12(s,3H,CH3), 2.65 (s, 3H, COCH3), 7.69 (s, 13 3. Diederich, F.; Stang, P. J. Metal Catalysed Cross Coupling 1H, Ar-H), 12.85 (s, 1H, OH). CNMR(CDCl3) d: 24.1, Reactions; Wiley-VCH: Weinheim, Germany, 1988. 87.3, 125.2, 129.4, 131, 153.2, 164.4, 198.4; MS m/z (M+) 4. (a) Larock, R. C.; Lee, N. H. J. Org. Chem. 1991, 56, 6253. 310.5; Anal. calcd for C H ClIO : C, 34.83; H, 2.5; X, 9 8 2 (b) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 52.33. Found: C, 34.79; H, 2.41; X, 51.94. 6689. (c) Busacca, C. A.; Johnson, R. E. Tetrahedron Lett. 1992, 33, 165. (d) Swenton, J. S.; Callinan, A.; Wang, S. J. 4-Hydroxy-5-iodo-3-methoxybenzaldehyde Org. Chem. 1992, 57, 78. -1 IR (cm ) umax: 2827 (C-H of CHO), 2739 (C-H of 5. Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1993, 32, 1 CHO), 1666 (-C=O), 1585 (C=C). HNMR(CDCl3) d: 1377. 6. Sovak, M. Radiocontrast Agents, Handbook of Experimen- 4.80 (s, 3H, OCH3), 7.34 (s, 1H, 2 Ar-H), 7.58 (s, 1H, 6 Ar-H), 8.06 (s, 1H, OH), 9.98 (s, 1H, CHO). 13CNMR tal Pharmacology; 73 Springer: Berlin, 1993. 7. (a) Heindel, N. D.; Burns, H. D.; Honds, T.; Brandy, L. W. (CDCl ) d: 58.3, 101.5, 116.3, 132.8, 138.3, 139.4, 165.7, 3 Chemistry of Radiopharmaceuticals; Masson: New York, 192.1; MS m/z (M+) 278; Anal. calcd for C H IO :C, 8 7 3 1997. (b) Ncolaou, K. C. Angew. Chem. Int. Ed. Eng. 1993, 34.53; H, 2.51; I, 45.68. Found: C, 34.48; H, 2.41; I, 45.72. 32, 1377. 8. Blatt, A. H. Org. Rect. 1942, 1, 342. 2-Hydroxy-3,5-diiodobenzaldehyde 9.Yang,S.G.;Kim,Y.H. Tetrahedron Lett. 1999, 40, 6051. -1 IR (cm ) umax: 2845 (C-H of CHO), 2719 (C-H of 10. Blackmore, I. J.; Boa, A. N.; Murray, E. J.; Dennis, M.; 1 1999 CHO), 1658 (-C=O), 1587 (C=C). HNMR(CDCl3) d: Woodward, S. Tetrahedron Lett. , 40, 6671. 1997 8.01 (s, 1H, 6 Ar-H), 8.13 (s, 1H, 4 Ar-H), 9.97 (s, 1H, 11. Noda, Y.; Kashima, M. Tetrahedron Lett. , 38, 6225. 13 12. Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron Lett. 1997, 38, CHO), 11.82 (s, 1H, OH). CNMR(CDCl3) d: 87.7, 94.5, 6305. 128.2, 140.9, 155.7, 168.5, 193; MS m/z (M+) 374; Anal. 13. Bardzil, L. C.; Cutler, C. J. J. Org. Chem. 1996, 61, 9621. calcd for C H I O : C, 22.45; H, 1.06; I, 67.91. Found: C, 7 4 2 2 14. Hubig, S. M.; Jung, W.; Kochi, J. K. J. Org. Chem. 1994, 59, 22.34; H, 1.72; I, 67.83. 6233. 15.Olah,G.A.;Qi,W.;Sandiford,G.;Prakash,G.K.S. J. Org. 2,4-Dihydroxy-3,5-diiodobenzaldehyde Chem. 1993, 58, 3194. -1 1994 IR (cm ) umax: 2811 (C-H of CHO), 2716 (C-H of 16. Bachky, A.; Forbelo, F.; Yus, M. Tetrahedron , 50, 1 CHO), 1648 (-C=O), 1575 (C=C). HNMR(CDCl3) d: 5139. 1990 7.86 (s, 1H, 6 Ar-H), 8.38 (s, 1H, OH), 10.08 (s, 1H, CHO), 17. Edgar, K. J.; Falling, S. N. J. Org. Chem. , 55, 5287. 874 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 Khansole et al.

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