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2782. I. Hachiya, M. Shimizu / Tetrahedron Letters 55 (2014) 2781–2788 ..... 5956–5968; (f) Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J..
Tetrahedron Letters 55 (2014) 2781–2788

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Chemoselective reductions and iodinations using titanium tetraiodide Iwao Hachiya ⇑, Makoto Shimizu ⇑ Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan

a r t i c l e

i n f o

Article history: Received 24 February 2014 Accepted 6 March 2014 Available online 19 March 2014 Keywords: Titanium tetraiodide Reduction Iodination Chemoselective CarbonAcarbon bond forming reaction

a b s t r a c t Titanium(IV) halides are extensively used in carbonAcarbon bond forming reactions as a Lewis acid and low valent titanium halides promote reductive coupling reactions of carbonyl compounds. In most of these reactions, ligands of titanium halides are chloride or bromide. On the other hand, titanium(IV) tetraiodide had been rarely used in organic synthesis until the late 1990s. Since 2000 several useful synthetic reactions have been developed utilizing a moderate Lewis acidity, reducing and iodination abilities of titanium(IV) tetraiodide. This digest summarizes examples of chemoselective reductions and iodinations using titanium(IV) tetraiodide (TiI4). Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pinacol coupling reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reformatsky-type reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reductive aldol and Mannich-type reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prins reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodoaldol reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-opening reaction of epoxides and cyclopropanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-Iodopyridine synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Titanium(IV) halides are extensively used in carbonAcarbon bond forming reactions; for examples, Mukaiyama aldol reactions of aldehydes with silyl enol ethers, Diels–Alder reactions, and carbonyl-ene reactions as a Lewis acid. Low valent titanium halides promote reductive coupling reactions of carbonyl compounds. In most of these reactions, ligands of titanium halides are chloride ⇑ Tel.: +81 59 231 9414; fax: +81 59 231 9413 (I.H.); tel./fax: +81 59 231 9413 (M.S.). E-mail addresses: [email protected] (I. Hachiya), [email protected]. ac.jp (M. Shimizu).

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or bromide.1 Although titanium(IV) tetraiodide had been used for the production of high purity metal titanium, its use was rare in organic synthesis. Titanium(IV) tetraiodide has a moderate Lewis acidity and is used as a promoter and a catalyst in Mannich-type reactions,2 and 1,4- and 1,2-double nucleophilic addition of ketene silyl acetals with a,b-unsaturated aldimines.3 On the other hand, titanium(IV) tetraiodide is different from titanium(IV) chloride or bromide in many reports and in particular shows reducing and iodination abilities in some useful organic reactions. Herein, this digest describes examples of chemoselective reductions and iodinations using titanium(IV) tetraiodide (TiI4).

http://dx.doi.org/10.1016/j.tetlet.2014.03.052 0040-4039/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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Scheme 1.

Reduction Pinacol coupling reaction Reactions using reducing ability of iodide anion are wellknown.4 Titanium(IV) tetraiodide is used as a chemoselective reducing agent; for examples, reduction of sulfoxides to sulfides,5 a-diketones to a-hydroxy ketones,6 and a-imino ketones to a-amino ketones (Scheme 1).7 Titanium(IV) tetraiodide promoted diastereoselective pinacol coupling reaction of aromatic aldehydes is reported; however, the reaction of aliphatic aldehydes does not proceed (Scheme 2).8 Nevertheless, the pinacol reaction of b-halogenated a,b-unsaturated aldehydes is promoted by titanium(IV) tetraiodide to give the coupling products in good yields with high dl-selectivities, and the subsequent reduction with H2/Pd-C gives saturated vic-diols in good yields (Scheme 3).9 Although two steps are needed, this pinacol-coupling/hydrogenation of b-halogenated a,b-unsaturated

Scheme 2.

Scheme 5.

Scheme 6.

aldehydes can be regarded as the pinacol-coupling reaction of aliphatic aldehyde to afford the saturated vic-diol in high dl-selectivity. It is known that b-halo free enals do not always undergo the efficient pinacol coupling reaction. A possible reaction pathway of titanium(IV) tetraiodide promoted pinacol coupling reaction is shown in Scheme 4. An initial iodination of the carbonyl group of the aldehyde 1 gives the iodinated intermediate 2, which is attacked by the iodide anion from titanium(IV) tetraiodide to form an anionic species. It has been reported that a similar halogenated intermediate was formed in the reaction of BCl3 with aromatic aldehydes.10 The species generated from reductive dehalogenation in turn undergoes addition to another aldehyde to form a pinacol product 3. The formation of iodinated intermediate 2 appears to be easy in the case of aldehydes with an electron-withdrawing substituent; therefore, the pinacol coupling reaction proceeds readily with b-halogenated a,b-unsaturated aldehydes. In 2008, titanium(IV) tetraiodide promoted pinacol coupling reaction of (Z)-3-iodo-3-trimethylsilylpropenal 4 was used for the preparation of trans-4,5-bis[(Z)-2-iodo-2-(trimethylsilyl)vinyl]-2,2-dimethyl-1,3-dioxolane 5, which was utilized for the subsequent CAC bond forming reactions (Scheme 5).11 Reformatsky-type reaction

Scheme 3.

Reformatsky reaction of a-haloesters with carbonyl compounds in the presence of zinc powder gives b-hydroxy carbonyl compounds and is well-known as one of the most important carbonAcarbon bond forming reactions. Reformatsky-type reaction promoted by some metal iodides such as AlI3,12 CeI3,13 and TiCl4/n-Bu4NI14 has been reported. Titanium enolates reductively

Scheme 4.

Scheme 7.

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Scheme 8.

Table 1 Deoxygenation of a-oxygenated ketone derivatives

R1

R2

R3

Yield (%)

4-MeC6H4 4-MeC6H4 4-MeC6H4 Ph Ph

H H H Me Me

Ac Bz Ts Ts Ms

74 74 80 85 80

Scheme 12.

In 2011, it was reported that titanium(IV) tetraiodide could reduce a-aetyloxy, benzoyloxy, mesyloxy, and tosyloxy ketones to produce deoxygenated ketones in good yields (Table 1). Reductive aldol reactions of a-tosyloxy ketones proceed with several aldehydes to afford the aldol products (Scheme 9).18 Reductive aldol and Mannich-type reactions

Scheme 9.

Scheme 10.

Reactions utilizing both iodination and reducing abilities are reported. In 2000, it was reported that ring-opening reaction of methoxyallene oxide, which was prepared from methoxyallene 6 with mCPBA in situ, with titanium(IV) tetraiodide generated the titanium enolate, and the subsequent reaction with aldehydes or acetals proceeded to give 3-hydroxy-2-methoxy or 2,3-dialkoxyketones in good yields (Scheme 10).19 The hemiacetal 9 is isolated as a byproduct in the above reaction, suggesting that it would be one of the intermediates. The subsequent reaction of 9 with benzaldehyde under the influence of TiI4-Ti(Oi-Pr)4 gives the aldol adduct 7 in high yield with high selectivity (Scheme 11). A plausible reaction mechanism is shown in Scheme 12. The titanium enolate 11 would be formed via ring-opening reaction of methoxyallene oxide 10 with diiododiisopropoxytitanium derived from titanium(IV) tetraiodide and titanium(IV) tetraisopropoxide and undergoes protonation with 3-chlorobenzoic acid to give iodo ketone 12. The iodo ketone 12 would be in turn regioselectively transformed into the titanium enolate 13 via reduction of the iodine with iodide anion, and the subsequent reaction with aldehyde gives the aldol adduct 7 in a regioselective manner. Since the development of the above-mentioned reductive aldol reaction via the small ring-opening reaction, several reductive al-

Scheme 11.

generated from a-iodoketones using titanium(IV) tetraiodide react with several aldehydes to give aldol products in good yields with good diastereoselectivities (Scheme 6).15 Titanium tetraiodide promotes an aza-Reformatsky-type reaction of a-iodomethyl ketone O-alkyl oximes with carbonyl compounds to give b-hydroxy ketone O-alkyl oximes in good to high yields (Scheme 7).16 Aza-Mannich-type reaction proceeds between imines and the aza-enolates formed from a-iodomethyl ketone O-alkyl oximes with titanium tetraiodide to give b-amino ketone O-alkyl oximes in good to excellent yields. Remarkable effects of added silica gel or molecular sieves (4 Å) are observed to promote the addition reactions (Scheme 8).17

Scheme 13.

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Scheme 14.

Scheme 15.

Table 2 Regioselectivity of the reductive ring-opening reaction of various 2-mono-substituted azetidin-3-ones

R

Yield (%)

15:16

Me Et i-Pr i-Bu Bn

89 66 76 97 82

95.5 83:17 77:23 63:37 92:8

products in good yields (Scheme 14).23 However, diastereoselectivities are moderate and the reaction of 2-acetylaziiridine gives the aldol product in low yield with low diastereoselectivity. In 2007, it was reported that aza-aldol reaction of aldehydes with aza-enolates, which was generated via reductive ring-opening of 2-(1-benzyloxyiminoethyl)aziridines with titanium(IV) tetraiodide, proceeded to give aza-aldol products in good yields with high diastereoselectivities (Scheme 15).24 a-Amino ketones are one of the most important nitrogen-containing compounds because of their use as versatile building blocks and intermediates for the synthesis of the biologically active compound synthesis.25 In 2010, it was reported that titanium(IV) tetraiodide-promoted ring-opening reactions of 2-mono-substituted azetidin-3-ones 14 gave a-amino ketones 15 in good yields with moderate to high regioselectivities (Table 2).26 On the other hand, reductive ring-opening reactions of 2,2disubstituted azetidin-3-ones 17 proceed at the more substituted bond to give the a-amino ketones 19 as sole products (Scheme 16). Regarding the different regioselectivity, two different pathways are proposed including an SN2-like process by titanium(IV) tetraiodide or a one-electron transfer promoted by low-valent titanium species. In the case of 2-mono-substituted azetidin-3-ones 14, the reaction would prefer an SN2-like process rather than one electron transfer, because radical stabilization is more depressed as compared with that of 2,2-disubstited cases. Initially, a-iodoketone 20 is generated via the ring-opening of azetidin-3-ones 14A or 14B attacked by the iodide anion at the less hindered site and subsequently another iodide anion attacks to the iodine to generate the titanium enolate species 21. Hydrolysis of the enolate 21 with water to quench the reaction gives the a-amino ketone 15 (Scheme 17). In the case of 2,2-dimethyl-azetidin-3-one 17a, it seems that an electron-transfer reaction would play a significant role (Scheme 18). Initially, the disproportionation of TiI4 gives lowvalent titanium species. One-electron transfer to azetidin-3-one 17a at the C-3 position gives a radical intermediate 22. A ringopening reaction proceeds via a fragmentation at the NAC(2) or NAC(4) bond. At this point, the fragmentation at the NAC(2) bond is favored because of the electronically more stabilized 2,2-dimethyl substitution. Further reduction of the intermediate leads to the corresponding titanium enolate. Also, the homolysis of the NAC(4) bond gives the less substituted enolate 24 (path A). Alternatively, the homolysis of the NAC(2) bond leads to the more substituted enolate 26 (path B). In path A, the enolate 24 could reverse to the azetidine 17a via a re-cyclization under an equilibrium.27 However, path B may not involve such a cyclization because of the steric hindrance. Finally, the more thermodynamically stable enolate 26 would predominate. The enolate 26 is hydrolyzed with water to give the a-amino ketone 19a. Enolates prepared by the reduction of 2-mono- or 2,2-disubstituted azetidin-3-ones react with an aldehyde or an imine to afford the aldol or Mannich-type products. This methodology provides a

Scheme 16.

dol or Mannich-type reactions are reported via chemoselective reductions (Scheme 13).20–22 These reductive carbonAcarbon bond forming reactions have an advantage of a procedure without isolation of unstable a-iodo carbonyl intermediates. In 2006, reductive ring-opening of N-tosylaziridines was carried out with titanium(IV) tetraiodide to form the titanium enolates, which in turn were subject to the aldol or the Manncich-type reactions with aldehydes or imines to give aldol or Manncich-type

Scheme 17.

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Scheme 21.

Table 4 TiI4-promoted ring-opening reaction of azetidin-3-one O-alkyloximes

Scheme 18. R

Me Et i-Bu

Scheme 19.

Table 3 TiI4–TiX4 (X = Br or Cl) promoted ring-opening reaction of 2-mono-substituted azetidin-3-ones

R

X

Temp

Yield (%)

15:16

Me Et i-Pr i-Bu Me Et i-Pr i-Bu

Br Br Br Br Cl Cl Cl Cl

78 °C to rt 78 °C to rt 78 °C to rt 20 to 10 °C 0 °C to rt 0 °C to rt 78 °C to rt 78 °C to rt

26 30 56 90 63 78 84 88

25:75 4:96 0:100 16:84 9:91 4:96 0:100 0:100

Scheme 20.

Yield (%) 31

32

15

16

0 0 0

0 0 0

2 1 0

51 35 28

straightforward access to 1,4-amino alcohols or diamines in a regioselective manner (Scheme 19). In 2012, it was reported that the ring-opening of 2-monosubstituted azetidin-3-ones at the more substituted bond occurred with the combined use of titanium(IV) tetraiodide and titanium(IV) tetrachloride or tetrabromide to give the a-amino ketones in moderate to high yields with high regioselectivities (Table 3).28 A proposed reaction mechanism is shown in Scheme 20. The disproportionation of titanium(IV) tetraiodide and titanium(IV) tetrachloride gives low-valent titanium species. A one-electron transfer to 2-mono-substituted azetidin-3-one 14 at the C-3 position gives a radical intermediate 27. The ring-opening reaction of 27 would proceed via a fragmentation at the NAC(2) bond to give the more substituted titanium enolate 29, which is more stable than the less substituted one, and the subsequent protonation with water to quench the reaction would give the corresponding a-amino ketone 15. The reductive aldol reaction of azetidin-3-one with chloral is carried out using titanium(IV) tetraiodide and titanium(IV) tetrachloride in the presence of Pd(O2CCF3)2 as a Lewis acid additive to afford the aldol product in good yield with syn-selectivity (Scheme 21).

Scheme 22.

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Scheme 23.

Titanium(IV) tetraiodide promoted ring-opening reaction of 2mono-substituted azetidin-3-one O-alkyloximes 30 proceeds at the more hindered site to give a-amino ketones (Table 4). In every reaction, a-amino ketones 15 and 16 are obtained instead of the desired a-amino ketone O-alkyloximes 31 or 32 probably due to the reductive cleavage of the NAO bond by titanium(IV) tetraiodide and subsequent hydrolysis with water to quench the reaction. Although the yields are low to moderate, it is of interest that the regioselectivity of the ring-opening reaction of 2-mono-substituted azetidin-3-one O-alkyloximes is different from that of the parent 2-mono-substituted azetidin-3-ones 14.29

Scheme 25.

Table 5 Prins reaction of alkyne with benzaldehyde dimethylacetal: comparison of titanium(IV) tetrahalide

Iodination Prins reaction Vinyl iodides are the most useful intermediates for the synthesis of multifunctionalized alkenes, which occur in biologically active compounds, and are applied to the metal-catalyzed crosscoupling and Nozaki–Hiyama–Kishi reactions as substrates.30 Iodinations of simple alkenes or phenyl acetylene with titanium(IV) tetraiodide give iodoalkanes and iodostylenes. On the other hand, iodinations of 1-alkynes afford 2,2-diiodoalkanes (Scheme 22).31 Titanium(IV) tetraiodide and iodine promote Prins-type reaction of acetals with alkenes to give 1,3-diiodopropopanes (Scheme 23).31 Intramolecular Prins reaction promoted by titanium(IV) tetraiodide proceeds to give the iodo bicyclic product in high diastereoselectivity (Scheme 24).32 Aza-Prins reactions of the imino ester 33 promoted by titanium(IV) tetraiodide and iodine with alkenes or alkynes proceed to give c-iodo-a-amino acid esters (Scheme 25).33 In 2010, titanium(IV) tetraiodide-promoted tandem Prins reaction of alkynes with acetals was reported. In the presence of titanium(IV) tetraiodide, tandem Prins reactions of alkynes proceed with acetals to give (Z,Z)-1,5-diodo-1,3,5-triarylpenta-1,4-dienes in good yields, where an intriguing reversal of the stereoselectivity is observed among titanium(IV) tetrahalides (Table 5).34 Iodoaldol reaction Since the iodoaldol reactions using TiCl4/n-Bu4NI or TiI4 reported by Tanigchi et al. in 1986 as shown in Scheme 26,35 several iodoaldol reactions have been reported via b-iodoallenoate intermediates from alkynyl ketones and esters with several metal iodides such as ZrCl4/n-Bu4NI,36 Et2AlI,37 MgI2,38 TMSI,39 BF3OEt2/ TMSI,40 CeCl37H2O/NaI,41 or GaI3.42 However, the diastereoselective iodoaldol reactions of internal alkynyl ketones have been limited to an intramolecular cyclization.43 In 2013, diastereoselective iodoaldol reaction of c-alkoxy-a,balkynyl ketone derivatives promoted by titanium(IV) tetraiodide was reported. Iodoaldol reactions of the c-diethoxy alkynyl ketone

Scheme 24.

X

Yield (%)

Ratio (Z,Z)/(Z:E)

F Cl Br I

0 67 68 68

— 4:96 11:89 91:9

Scheme 26.

Table 6 Iodoaldol reaction with different aldehydes O

Til4 (1.3 equiv) RCHO (1.0 equiv)

Ph

OEt

CH 2Cl 2, –50 °C, 2 h

O Ph EtO

OEt

R I OEt

34

OH

E-35

O

+

OH

Ph

R OEt

I

OEt

Z-35

R

Yield (%)

E/Z

Ph p-ClC6H4 p-MeOC6H4 p-MeC6H4 1-Naphthyl 2-Thienyl Cl3C n-Pentyl

65 52 61 64 34 52 41 35

97:3 100:0 100:0 89:11 100:0 100:0 100:0 100:0

34 with several aldehydes proceed to give the iodoaldol products 35 in moderate yields with high diastereoselectivities (Table 6).44 The iodoaldol reactions using c-methoxymethoxy alkynyl ketones 36 as a c-monoalkoxyalkynyl ketone also work well. The reaction of c-methoxymethoxy alkynyl aryl ketones affords the iodoaldol products 37 in moderate to good yields with good to high diastereoselectivities except in the case of 1-naphthaldehyde. Although the reaction of c-methoxymethoxy alkynyl methyl ketones proceeds, the iodo product 37 is obtained in low yield with low diastereoselectivity (Table 7).

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Scheme 30.

R2

R1

Yield (%)

E/Z

Ph Ph Ph Ph Ph Ph 2-Thienyl Me

p-ClC6H4 p-MeOC6H4 p-MeC6H4 1-Naphthyl 2-Thienyl n-Pentyl Ph Ph

72 56 73 31 33 48 74 32

75:25 88:12 79:21 56:44 85:15 70:30 75:25 56:44

O

OH

Ph EtO

Ph

Pd(PPh 3) 2Cl 2 (5.0 mol%) CuI (0.2 equiv) phenylactetylene (2.0 equiv)

O

OEt

Ph

OEt

E-38

Ph

39 73% O

PdCl 2(CH 3CN) 2 (20 mol%) THF, reflux, 2 h

O

Ph

Ph EtO

+

O

Ph

Ph I

Pd(PPh 3) 2Cl 2 (5.0 mol%) CuI (0.2 equiv) phenylactetylene (2.0 equiv)

O Ph

O

40 18% OH

Ph

Ph H

Ph

OEt

O

OH

Ph EtO

DMF/Et 3N (1:1), 90 ºC, 20 h

I

Table 8 2-Iodopyridine synthesis

41 36% O Ph

Ph O

DMF/Et 3N (1:1), 60 ºC, 6 d

MOMO

MOMO

E-42

Ph

Scheme 31.

43 49%

Scheme 27.

furans 40 and 41. The transformation of the iodo product E-42 directly produces the furan 43 (Scheme 27). Ring-opening reaction of epoxides and cyclopropanes

Scheme 28.

Scheme 29.

The iodoaldol products are transformed into tetrasubstituted furans via the enynol intermediate. The Sonogashira coupling of the iodo product E-38 with phenylacetylene in the presence of [PdCl2(PPh3)2] and CuI proceeds to give the enynol 39 in 73% yield. The cyclization reaction of enynol 39 with [PdCl2(PPh3)2] affords

Titanium(IV) tetraiodide promotes the ring-opening reaction of epoxides and cyclopropanes to give iodinated products. The ringopening reaction of epoxide 44 with titanium(IV) tetraiodide gives iodohydrin 45 in high yield (Scheme 28).45 The ring-opening reaction of 1-hydroxyspiro[5.2]cyclooct-4-en3-one 46 by titanium(IV) tetraiodide affords the iodoethylbenzoate 47 (Scheme 29).46 The reaction of gem-aryl-disubstituted methylenecyclopropane 48 with TiI4/diethyl azodicarboxylate gives the diiodo ring-opened product 49 in high yield (Scheme 30).47 2-Iodopyridine synthesis In 2009, it was reported that highly substituted 2-iodopyridines 51 were synthesized from 2-(2-cyanoalk-1-enyl)-b-keto esters 50 under the influence of titanium(IV) tetraiodide that worked efficiently for iodination–cyclization (Table 8).48 The present iodination–cyclization reaction most probably proceeds as shown in Scheme 31. The titanium intermediate 52 would be formed via a nucleophilic addition of iodide anion to a cyano group. Subsequent intramolecular cyclization of this species 52 would give a titanium alkoxide intermediate 53, which would undergo aromatization via elimination of titanium oxide to give 2iodopyridine 51.

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Conclusion This digest describes several attractive reactions utilizing chemoselective reductions and iodinations using titanium(IV) tetraiodide. Although reducing ability of iodide anion is wellknown, titanium(IV) tetraiodide promotes not only chemoselective reduction but also reductively generates enolates or aza-enolates, which react with aldehydes, acetals, and imines to give useful synthetic intermediates. On the other hand, titanium(IV) tetraiodide also promotes iodination reactions to give iodinated products. These iodination reactions will be applied to the synthesis of biologically active compounds and functional materials because iodinated products synthesized from unsaturated compounds can be transformed into multi-functionalized compounds using transition metal catalyzed coupling and Nozaki–Hiyama–Kishi reactions. Acknowledgements This work was supported by Grants-in Aid for Scientific Research (B) and Innovative Areas ‘Organic Synthesis Based on Reaction Integration. Development of New Methods and Creation of New Substances’ from JSPS and MEXT. References and notes 1. (a) Mukaiyama, T. Org. React. 1982, 28, 203–331; (b) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986; (c) Narasaka, K. Synthesis 1991, 1–11; (d) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021–1050. 2. (a) Shimizu, M.; Kume, K.; Fujisawa, T. Tetrahedron Lett. 1995, 36, 5227–5230; (b) Shimizu, M.; Kume, K.; Fujisawa, T. Chem. Lett. 1996, 545–546. 3. Shimizu, M.; Morita, A.; Kaga, T. Tetrahedron Lett. 1999, 40, 8401–8405. 4. (a) Zincke, T.; Baeuer, J. Liebigs Ann. Chem. 1918, 416, 86–112; (b) Reusch, W.; Lemahieu, R. J. Am. Chem. Soc. 1964, 86, 3068–3072. 5. Shimizu, M.; Shibuya, K.; Hayakawa, R. Synlett 2000, 1437–1438. 6. Hayakawa, R.; Sahara, T.; Shimizu, M. Tetrahedron Lett. 2000, 41, 7939–7942. 7. Shimizu, M.; Sahara, T.; Hayakawa, R. Chem. Lett. 2001, 792–793. 8. (a) Hayakawa, R.; Shimizu, M. Chem. Lett. 2000, 724–725; Titanium(IV) tetraiodide is reduced with copper to give low valent species which can be used for the pinacol coupling reaction, see: (b) Mukaiyama, T.; Yoshimura, N.; Igarashi, K. Chem. Lett. 2000, 838–839; (c) Mukaiyama, T.; Yoshimura, N.; Igarashi, K.; Kagayama, A. Tetrahedron 2001, 57, 2499–2506. 9. Hayakawa, R.; Goto, H.; Shimizu, M. Org. Lett. 2002, 4, 4097–4099. 10. Kabalka, G. W.; Wu, Z. Tetrahedron Lett. 2000, 41, 579–581. 11. Shimizu, M.; Okimura, H.; Manabe, N.; Hachiya, I. Chem. Lett. 2008, 37, 28–29. 12. Borah, H. N.; Boruah, R. C.; Sandhu, J. S. J. Chem. Soc., Chem. Commun. 1991, 154–155. 13. Fukuzawa, S.; Tsuruta, T.; Fujinami, T.; Sakai, S. J. Chem. Soc., Perkin Trans. 1 1987, 1473–1477. 14. Tsuritani, T.; Ito, S.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2000, 65, 5066– 5068. 15. (a) Shimizu, M.; Kobayashi, F.; Hayakawa, R. Tetrahedron 2001, 57, 9591–9595; Titanium(IV) tetraiodide is reduced with copper to give low valent species which can be used for Reformatsky-type reaction, see: (b) Arai, H.; Shiina, I.; Mukaiyama, T. Chem. Lett. 2001, 118–119. 16. Shimizu, M.; Toyoda, T. Org. Biomol. Chem. 2004, 2, 2891–2892. 17. Shimizu, M.; Tanaka, M.; Itoh, T.; Hachiya, I. Synlett 2006, 1687–1690. 18. Hachiya, I.; Inagaki, T.; Ishihara, Y.; Shimizu, M. Bull. Chem. Soc. Jpn. 2011, 84, 419–421. 19. Hayakawa, R.; Shimizu, M. Org. Lett. 2000, 2, 4079–4081. 20. Shimizu, M.; Takeuchi, Y.; Sahara, T. Chem. Lett. 2001, 1196–1197. 21. Shimizu, M.; Sahara, T. Chem. Lett. 2002, 888–889.

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