HETEROCYCLES

Communication | Special issue | Vol. 79, No. 1, 2009, pp. 365-371
Received, 25th September, 2008, Accepted, 27th November, 2008, Published online, 1st December, 2008.
DOI: 10.3987/COM-08-S(D)32

■ Titanium Tetraiodide Induced Cyclization of 2-(2-Cyanoalk-1-enyl)-β-keto Esters into 2-Iodopyridines

Iwao Hachiya, Yushi Minami, and Makoto Shimizu*

Department of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Tsu, Mie 514-8507, Japan

Abstract

Highly substituted 2-iodopyridines were synthesized from 2-(2-cyanoalk-1-enyl)-β-keto esters under the influence of titanium tetraiodide that worked efficiently for iodination-cyclization.

Among the pyridine derivatives 2-halopyridines have been utilized as useful intermediates for the nucleophilic displacements of halogens with several nucleophiles and for the lithiation with n-butyllithium at low temperature to generate lithiopyridines, which react with several electrophiles.1 During investigation into the intriguing heterocyle formations using conjugate addition reactions to alkynyl imines2 and their ketone analogues,3 we found a facile 2-iodopyridine formation from 2-(2-cyanoalk-1-enyl)-β-keto esters with titanium tetraiodide which has both a good iodination ability and mild Lewis acidity. This paper reports a short-step 2-iodopyridine synthesis.

Regarding other nitrogen-containing heterocycles, we found that the decarboxylation-cyclization reaction of 2-(2-cyanoalk-1-enyl)-β-keto ester (1)4 gave 2-iminopyrone (2) (Scheme 1). The decarboxylation was carried out in the presence of one equivalent of sodium chloride in DMSO-H2O (50:1) at 150 oC for 20 h to give 2-iminopyrone (2) in 34% yield.3b,5 Decarboxylation reactions using other metal chlorides such as LiCl and KCl did not improve the yield of 2-iminopyrone (2). Since iodide anion often induced removal of an allylic moiety, decarboxylation-cyclization reaction of β-keto allyl ester (3) was next examined using TiI4 by a reaction mechanism as shown in Scheme 2.6 The reaction of cyano-β-keto allyl ester (3) with TiI4 (1.7 equiv) was carried out in CH2Cl2 at rt for 20 h to give 2-iodopyridine (4) in 12% yield along with the recovered cyano-β-keto allyl ester (3) in 52% yield (Table 1, entry 1). Although 2-iminopyrone (2) was not obtained, the present 2-iodopyridine synthesis was investigated in detail due to the importance of this class of compounds.7,8 On the other hand, the reaction of cyano-β-keto allyl ester (3) with TiCl4 (1.0 equiv) or TiBr4 (1.7 equiv) did not give the 2-chloro or 2-bromopyridines, and β-keto allyl ester (3) was recovered in 97% and 93% yields, respectively. In order to improve the yield of the 2-iodopyridine (4), the use of additives was next examined. When Ti(OiPr)4 was used as an additive, 2-iodopyridine (4) was obtained in 32% yield (entry 2).9 Although other titanium alkoxides were examined, the product yields were not satisfactory (entries 2-6). Among other additives besides titanium alkoxides, salicylic acid was found to be the most effective.9a When both Ti(OEt)4 (0.25 equiv) and salicylic acid (1.0 equiv) were used as additives, 2-iodopyridine (4) was obtained in 52% yield (entry 7). Finally, the combined use of Ti(OEt)4 (0.25 equiv) and salicylic acid (2.0 equiv) as additives gave 2-iodopyridine (4) in 61% yield (entry 8).

The present iodination-cyclization reaction most probably proceeds as shown in Scheme 3. The titanium intermediate (5) would be formed via a nucleophilic addition of iodide ion to cyano group. Subsequent intramolecular cyclization of this species (5) would give a titanium alkoxide intermediate (6), which would undergo aromatization via elimination of titanium oxide to give 2-iodopyridine (4).10

Several examples of the present 2-iodopyridine (8) synthesis were examined. Table 2 summarizes the results.11 The reaction of β-tert-butyl keto esters (7) gave 2-iodopyridines (8a), (8b), and (8c) in moderate yields, respectively (entries 1-3), whereas the reaction of β-phenyl keto ester (7d) gave 2-iodopyridine (8d) in 25% yield (entry 4).

In conclusion, we have found a new synthetic route of multi-substituted 2-iodopyridines by the reaction of 2-(2-cyanoalk-1-enyl)-β-keto ester with TiI4. The present method is an attractive synthetic route of multi-substituted 2-iodopyridines because 2-(2-cyanoalk-1-enyl)-β-keto esters are readily prepared as a cyclization precursor from cyanoacetate derivatives and alkynyl ketones, and furthermore, a 2-iodo substituent can be transformed into other functional groups such as alkoxy,12 alkynyl,13 aryl,14,15 arylsulfanyl,15 or allyl15 groups.

References

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2. (a) I. Hachiya, K. Ogura, and M. Shimizu, Org. Lett., 2002, 4, 2755; CrossRef (b) I. Hachiya, K. Ogura, and M. Shimizu, Synthesis, 2004, 1349; CrossRef (c) I. Hachiya, M. Atarashi, and M. Shimizu, Heterocycles, 2006, 67, 523; CrossRef (d) I. Hachiya, Y. Minami, T. Aramaki, and M. Shimizu, Eur. J. Org. Chem., 2008, 1411. CrossRef
3. (a) I. Hachiya, H. Shibuya, and M. Shimizu, Tetrahedron Lett., 2003, 44, 2061; CrossRef (b) I. Hachiya, H. Shibuya, K. Hanai, and M. Shimizu, Lett. Org. Chem., 2004, 1, 349. CrossRef
4. 2-(2-Cyanoalk-1-enyl)-β-keto ester (1) was prepared from ethyl 2-cyanopropanoate (9) with alkynyl ketone (10) as shown in Scheme 4. .
5. (a) A. P. Krapcho, Synthesis, 1982, 805; CrossRef (b) A. P. Krapcho, Synthesis, 1982, 893. CrossRef
6. Use of TiI4 for iodination, see: (a) M. Shimizu, T. Toyoda, and T. Baba, Synlett, 2005, 2516; CrossRef M. Shimizu, T. Baba, S. Todou, and I. Hachiya, Chem. Lett., 2007, 36, 12, and references therein. CrossRef
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8. For recent synthesis of highly substituted pyridines, see: (a) J. R. Manning and H. M. L. Davies, J. Am. Chem. Soc., 2008, 130, 8602; CrossRef (b) D. A. Colby, R. G. Bergman, and J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 3645; CrossRef (c) J. Barluenga, M. Á. Fernández-Rodríguez, P. García-García, and E. Aguilar, J. Am. Chem. Soc., 2008, 130, 2764; CrossRef (d) K. Parthasarathy, M. Jeganmohan, and C.-H. Cheng, Org. Lett., 2008, 10, 325; CrossRef (e) M. Movassaghi, M. D. Hill, and O. K. Ahmad, J. Am. Chem. Soc., 2007, 129, 10096; CrossRef (f) B. M. Trost and A. C. Gutierrez, Org. Lett., 2007, 9, 1473; CrossRef (g) M. D. Fletcher, T. E. Hurst, T. J. Miles, and C. J. Moody, Tetrahedron, 2006, 62, 5454; CrossRef (h) M. Movassaghi and M. D. Hill, J. Am. Chem. Soc., 2006, 128, 4592; CrossRef (i) K. Tanaka, N. Suzuki, and G. Nishida, Eur. J. Org. Chem., 2006, 3917; CrossRef (j) Y. Yamamoto, K. Kimpara, R. Ogawa, H. Nishiyama, and K. Itoh, Chem. Eur. J., 2006, 12, 5618; CrossRef (k) M. M. McCormick, H. A. Duong, G. Zuo, and J. Louie, J. Am. Chem. Soc., 2005, 127, 5030; CrossRef For a example of the synthesis of a 2-iodopyridine, see: (l) D. Suzuki, R. Tanaka, H. Urabe, and F. Sato, J. Am. Chem. Soc., 2002, 124, 3518, and references therein. CrossRef
9. (a) R. Hayakawa and M. Shimizu, Org. Lett., 2000, 2, 4079; CrossRef (b) M. Shimizu, M. Tanaka, T. Itoh, and I. Hachiya, Synlett, 2006, 1687. CrossRef
10. Although the roles of titanium tetraalkoxide and salicylic acid are not yet clear, we presume that a ligand exchange of titanium alkoxide intermediate (6) with salicylic acid would occur to generate titanium salicylate intermediate (11), which would undergo aromatization via elimination of titanium oxide by deprotonation with titanium tetraalkoxide as a base to give 2-iodopyridine (4) as shown in Scheme 5.
11. To a suspension of TiI4 (194 mg, 0.35 mmol) in CH2Cl2 (0.5 mL) was added successively Ti(OEt)4 (0.050 mL, 0.050 mmol, 1.0 M in CH2Cl2) and a solution of 7c (61.5 mg, 0.20 mmol) in CH2Cl2 (1.5 mL) at rt. The resulting mixture was stirred at rt for 3 h. The reaction was quenched with sat. aq. NaHCO3 and 5% aq. NaHSO3. The mixture was filtrated through a Celite pad. The layers were separated and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with sat. aq. NaHCO3 and brine, and then dried over anhydrous Na2SO4. Purification on silica gel TLC (n-hexane/EtOAc = 10/1) gave the 2-iodopyridine (8c) (30.0 mg, 36% (65% conversion yield)) and the recovered β-keto ester (7c) (27.1 mg, 44%). 8c: White solid. Mp 108.5-109.5 oC. 1H NMR (500 MHz, CDCl3): δ = 7.34-7.43 (m, 3H), 7.11-7.15 (m, 2H), 3.80 (q, J = 7.3 Hz, 2H), 2.10 (s, 3H), 1.38 (s, 9H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ = 168.6, 162.2, 147.8, 137.2, 133.7, 128.6, 128.1, 128.1, 125.6, 61.0, 39.2, 30.0, 24.1, 13.3. IR (KBr): 3060, 2982, 2967, 2937, 1729, 1540, 1518, 1489, 1463, 1442, 1403, 1365, 1259, 1231, 1205, 1194, 1151, 1076, 1016, 948, 863, 752, 701, 639, 583 cm-1. HRMS (EI): calcd. for C19H22INO2 423.0695 [M]+; found 423.0703.
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13. For recent examples of transformation into alkynyl groups, see: (a) J. D. Crowley, D. A. Leigh, P. J. Lusby, R. T. McBurney, L.-E. Perret-Aebi, C. Petzold, A. M. Z. Slawin, and M. D. Symes, J. Am. Chem. Soc., 2007, 129, 15085; CrossRef (b) C. Engtrakul and L. R. Sita, Organometallics, 2008, 27, 927; CrossRef (c) M. F. Martínez-Esperón, D. Rodríguez, L. Castedo, and C. Saá, Tetrahedron, 2008, 64, 3674. CrossRef
14. For a recent example of transformation into aryl groups, see: C. A. Main, H. M. Petersson, S. S. Rahman, and R. C. Hartley, Tetrahedron, 2008, 64, 901. CrossRef
15. For a recent example of transformation into arylsulfanyl or allyl groups, see: W. Lin, L. Chen, and P. Knochel, Tetrahedron, 2007, 63, 2787. CrossRef