No.156 No.156

ScienceScience "Winter""Winter" SeminarSeminar

Carbonyl Olefination (1)

Takeshi Takeda

Department of Applied Chemistry, Tokyo University of Agriculture and Technology

1. Introduction Horner–Wadworth–Emmons reaction using organophosphorous compounds,3) two Julia reactions (the Julia-Lythgoe and Julia- In 1953, Wittig and Geissler reported that olefins were Kocienski reactions, see the column on the next page) using produced by the reaction of phosphonium ylides with carbonyl organosulfur compounds,4) and the Peterson reaction using compounds.1) This reaction, now known as the Wittig reaction,2) organosilicon compounds,5) have been developed for this enjoys a great advantage in that no ambiguity exists as to the transformation (Scheme 1). Depending on their characteristic location of the double bond in the product. Since the discovery reactivity and selectivity, these reactions are employed for the of the Wittig reaction, the transformation of a C=O double synthesis of various organic molecules. bond of the carbonyl compound into a C=C double bond, often Despite these extensive studies, many problems still remain called as carbonyl olefination, has been extensively studied unsolved in carbonyl olefination. In this article, some of these as one of the most important methods for the construction problems are discussed along with our results of the study on of carbon skeletons. Thus a variety of reactions, such as the this issue.

R4

3 R PR3 1 Wittig reaction

R4

3 R POR2 Horner-Wadsworth-Emmons reaction

1 4 O R4 R R

R1 R2 3 2 3 R SO2Ar R R

Julia reaction (Na/Hg)

R4

R3 SiR 3 Peterson reaction

Scheme 1

2. Tetrasubstituted Olefins tetrasubstituted olefins via azines (Scheme 2),6) in which he described that “the Wittig reaction has been widely used in the One of the serious drawbacks remaining in the Wittig and preparation of disubstituted olefins, but yields are lower in the Horner–Wadsworth–Emmons reactions is that they cannot be case of trisubstituted olefins, and generally very low (often not employed for the transformation of ketones into tetrasubstituted reported) in case of tetrasubstituted olefins.” olefins. In 1972, Barton reported the multistep synthesis of 6 No.156

The transformation of ketones into trisubstituted olefins is Julia reactions. As for the Peterson reaction, preparations of also recognized to be difficult under the standard conditions of certain tetrasubstituted olefins containing a carbo- or heterocycle the Julia-Lythgoe reaction, and it can only be achieved by the have been reported. However the yields are generally low as modification using SmI2 instead of Na(Hg) for the reduction of compared with the formation of corresponding trisubstituted β-acyloxy sulfones (Scheme 3).7) Furthermore, there seems to olefins (Scheme 4).8) be no report on the preparation of tetrasubstituted olefins by the

O H NNH H S Pb(OAc) P(OEt) 2 2 N 2 HN 4 N 3 2 S S 74% N 100% HN 99% N 75%

Scheme 2

OCOPh O 1) Hex SO2Ph / BuLi SmI Hex 2 Ph Hex Ph Ph 2) PhCOCl SO2Ph 81% 72% E:Z = ca. 2:1 Scheme 3

O

O SiMe3 / LDA O O R R = H 89% O Ph R Ph R = Me 50% Scheme 4

Two “Julia” Reactions

Although the names and reagents used are similar to each other, their reaction pathways are completely different. In 1973, Marc Julia and Jean-Marc Paris reported the carbonyl olefination using a-lithio sulfones 1.1) Later on, this “Julia” reaction was extensively studied by Lythgoe and Kocienski, and hence it is also called the Julia-Lythgoe reaction. The reaction was carried out in a same reaction vessel, but the reaction essentially consists of two steps, the addition of 1 to carbonyl compounds followed by acetylation and the reductive elimination of the resulting b-acetoxy sulfones 2. Another “Julia” reaction named the Julia-Kocienski reaction was first reported by Sylvestre Julia in 19912) and extensively studied by Kocienski and co- workers. The reaction proceeds through the addition of a-lithio sulfones 1 to carbonyl compounds, the subsequent Smiles rearrangement, and elimination of sulfur dioxide and aryloxide.

Julia-Lythgoe reaction O 3 3 1 3 4 R R 1 3 R R R PhO2S R4 AcCl PhO2S R4 Na(Hg) R R PhSO2 1 1 2 R R 2 4 R R2 O R2 OAc R R 1 2

Julia-Kocienski reaction O 1 R3 R R3 R4 ArO2S R4 Smiles rearrangement ArSO 2 R1 R2 2 O R 3 1

- R3 1 3 O2S R4 R R N N N 1 Ar = R - 2 4 N N 2 OAr - SO2, ArO R R N ,,S R R

1) M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 4833. 2) J. B. Baudin, G. Hareau, S. A. Julia, O. Ruel, Tetrahedron Lett. 1991, 32, 1175.

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The most powerful tool to synthesize highly sterically- however, suffers several limitations. For example, the selective congested tetrasubstituted olefins would be the low-valent preparation of unsymmetrical olefins by the cross-coupling of titanium mediated reductive coupling of ketones (the McMurry two distinct ketones is generally difficult even though one of coupling).9) Although the preparation of ethylene bearing the coupling components is employed in large excess (Scheme four tert-butyl groups has not appeared yet, highly sterically 7). Therefore, a new efficient method for the transformation of crowded olefins such as those shown in Schemes 510) and ketones into highly substituted olefins is still required. 611) were prepared by the McMurry coupling. The reaction,

TiCl3(DME)1.5-Zn/Cu TiCl3-LiAlH4 2 O 2 O 87% 13%

Scheme 5 Scheme 6

O O TiCl3 / Li + +

(4 equiv) 50% 26% Scheme 7

3. Olefination of Carboxylic Acid Derivatives yields. The preferential carbonyl olefination shown in Scheme 9 is attributable to the conformation of starting material favorable Although numerous efforts have been devoted to develop to the formation of cyclic structure and a conjugated system the methods for the transformation of carboxylic acid derivatives stabilizing the olefination product. into heteroatom-substituted olefins, this transformation still remains problematic. Unlike the carbonyl olefination of Some additional examples are depicted in Schemes 10,15) aldehydes and ketones, it is recognized that the Wittig reaction 11,16) 12,17) and 13.18) The carbonyl compounds employed in cannot be employed for the olefination of carboxylic acid these reactions are restricted to formats and carboxylic acid derivatives such as esters due to the preferential acylation of derivatives bearing an electron withdrawing group such as ylides. However, as shown in Schemes 8 and 9, whether the perfluoroalkyl and acyl groups. These reactions are referred to acylation (Scheme 8)13) or carbonyl olefination (Scheme 9)14) as the non-classical Wittig reaction19) and often employed for is preferred is largely dependent on the structure of substrates the synthesis of heterocyclic compounds as indicated in the last and, in certain cases, the process is synthetically useful for the example. preparation of heteroatom-substituted olefins in reasonable

O O O O O PPh3 O PPh3 O Ph3P OEt 84% O 60% O OMe OMe Scheme 8 Scheme 9

O CF3 O O O O O CF3 PPh3 OO Ph PPh O 3 O AcO OAc AcO OAc Ph 65% 65% OAc OAc Scheme 10 Scheme 11

PhOCH CONH PhOCH CONH PPh3 2 S 2 S Ph3P CO2Me NHOBn O N N MeO C O 67% 2 NHOBn S CO Bn CO Bn S 86% 2 E:Z = 1:1 2

Scheme 12 Scheme 13

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The McMurry coupling is generally applied to the reductive often employed for the synthesis of natural products such as coupling of aldehydes and ketones, but in certain cases, the alkaloids. reaction is also effective for the cross-coupling of esters and amides with ketones or aldehydes. Although the preparation Several other reagents have also been developed for the of enol ethers and enamines by the intermolecular McMurry olefination of carboxylic acid derivatives24) which include the coupling were reported (Schemes 1420) and 1521)), these organometallic species generated from the gem-dibromides- 25) reactions should be considered as exceptional. In contrast, the TiCl4-Zn-TMEDA system (Scheme 18) and gem-dizinc intramolecular McMurry coupling is useful for the preparation compounds (Scheme 19).26) of benzofurans (Scheme 16)22) and indoles (Scheme 17)23) and

O OEt OEt O TiCl -LiAlH , Et N 3 4 3 SBu-t + 60% t-BuS Scheme 14

O MeO Ph O Sm-SmI2 NEt2 + Ph Ph Ph 75% MeO NEt2 Scheme 15

O O MeO OMe H TiCl3-C8K MeO Ph MeO NH TiCl3-C8K O 89% O OMe O 86% MeO N H O Ph OMe

OMe Scheme 16 Scheme 17

Br

/ Zn / TiCl4 O Br MeO

Ph OMe Ph TMEDA 61% E:Z = 10:90 Scheme 18

O CH2(ZnI)2

OPr-i OPr-i β-TiCl3 / TMEDA 90% Scheme 19

As described above, various reagents can be employed to titanocene 5 (Scheme 21)30) are also powerful tools for the perform the carbonyl olefination of carboxylic acid derivatives, preparation of heteroatom substituted olefins from carboxylic but the most promising reagent for this transformation would acid derivatives. The formation of such alkylidene complexes be titanium-carbene complexes. Since methylidenetitanocene 2 by α-elimination of dialkyltitanocenes, however, still remains a generated from the Tebbe reagent 3 was found to methylidenate serious problem in that it cannot be applied for the preparation carbonyl compounds in 1978,27) Pine, Grubbs, Petasis, and of alkylidene complexes bearing a β-hydrogen. many other researchers studied the carbonyl olefination using titanium carbene complexes.28) The carbene complex 2 is the In order to overcome all these drawbacks of conventional most frequently employed reagent for the methylidenation of reactions, we have studied a new carbonyl olefination utilizing carboxylic acid derivatives, and numerous applications have a wide variety of titanium carbene complexes generated by appeared as exemplified in Scheme 20.29) Titanium-alkylidene the desulfurizative titanation of thioacetals. The details of our complexes such as 4 generated from bis(trimethylsilylmethyl) results on this study will be discussed next. 9 No.156 No.156

O TiCp2 CH2 2 OEt OEt

O TiCp AlMe 2 2 81% Cl 3

Scheme 20

SiMe3 Cp2Ti 4

SiMe3 O O SiMe3 O Cp Ti 2 67% E:Z = 2.5:1 SiMe3 5 Scheme 21

References 17) M. L. Gilpin, J. B. Harbridge, T. T. Howarth, J. Chem. Soc., Perkin Trans. 1 1987, 1369. 1) G. Wittig, G. Geissler, Liebigs Ann. 1953, 580, 44. 18) C. N. Hsiao, T. Kolasa, Tetrahedron Lett. 1992, 33, 2629. 2) A. Maercker, Org. React. 1965, 14, 270. 19) P. J. Murphy, S. E. Lee, J. Chem. Soc., Perkin Trans. 1 3) W. S. Wadsworth, Jr., Org. React. 1977, 25, 73. 1999, 3049. 4) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1 2002, 2565. 20) S. Sabelle, J. Hydrio, E. Leclevc, C. Mioskowski, P.-Y. 5) D. J. Ager, Org. React. 1990, 38, 1. Renardo, Tetrahedron Lett. 2002, 43, 3645. 6) D. H. R. Barton, B. Willis, J. Chem. Soc., Perkin Trans. 1 21) X. Xu ,Y. Zhang, Tetrahedron 2002, 58, 503. 1972, 305. 22) A. Fürsner, D. N. Jumbam, Tetrahedron 1992, 48, 5991. 7) I. Marko, F. Murphy, S. Dolan, Tetrahedron Lett. 1996, 37, 23) A. Fürsner, D. N. Jumbam, G. Seidel, Chem. Ber. 1994, 2089. 127, 1125. 8) G. L. Larson, R. M. Betancourt de Perez, J. Org. Chem. 24) T. Okazoe, K. Takai, K. Oshima, K. Utimoto, J. Org. Chem. 1985, 50, 5257. 1985, 52, 4410. 9) J. E. McMurry, Chem. Rev. 1989, 89, 1513; M. Ephritikhine, 25) S. Matsubara, K. Ukai, T. Mizuno, K. Utimoto, Chem. Lett. C. Villiers, in Modern Carbonyl Olefination, ed. by T. 1999, 825. Takeda, Wiley-VCH, Weinheim, 2004, p. 223. 26) S. Matsubara, K. Oshima, in Modern Carbonyl Olefination, 10) J. E. McMurry, T. Lectka, J. G. Rico, J. Org. Chem. 1989, ed. by T. Takeda, Wiley-VCH, Weinheim, 2004, p. 200. 54, 3748. 27) F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. 11) G. Böhrer, R. Knorr, Tetrahedron Lett. 1984, 25, 3675. Soc. 1978, 100, 3611. 12) J. E. McMurry, L. R. Krepski, J. Org. Chem. 1976, 41, 28) S. H.Pine, Org. React. 1993, 43, 1; N. A. Petasis, in 3929. Transition Metals for Organic Synthesis, eds. by M. Beller, 13) H. O. House, H. Babad, J. Org. Chem. 1963, 28, 90. C. Bolm, Wiley-VCH, Weinheim, 1999, p. 361; T. Takeda, 14) H. J. Bestmann, D. Roth, Angew. Chem., Int. Ed. 1990, 29, A.Tsubouchi, in Modern Carbonyl Olefination, ed. by T. 99. Takeda, Wiley-VCH, Weinheim, 2004, p. 151. 15) B. Beagley, D. S. Larsen, R. G. Pritchard, R. J. Stoodley, J. 29) S. H. Pine, R. Zahler, D. A. Evans, R. H. Grubbs, J. Am. Chem. Soc., Perkin Trans. 1 1990, 3113. Chem. Soc. 1980, 102, 3270. 16) J. P. Bégué, D. Bonnet-Delpon, S. W. Wu, A. M’Bida, T. 30) N. A. Petasis, I. Akiritopoulou, Synlett 1992, 665. Shintani, T. Nakai, Tetrahedron Lett. 1994, 35, 2907.

Introduction of the authors :

Takeshi Takeda Professor, Department of Applied Chemistry, Tokyo University of Agriculture and Technology

Takeshi Takeda obtained his Ph.D. (1977) in chemistry from Tokyo Institute of Technology. He joined the University of Tokyo as an Assistant Professor in 1977. After a half year of postdoctoral work at University of California, Los Angeles, he moved to Tokyo University of Agriculture and Technology as an Associate Professor in 1981. He was appointed to a Professorship in 1994. He received an Incentive Award in Synthetic Organic Chemistry, Japan (1987) and a Chemical Society of Japan Award for Creative Work (2003). His current research interests include organic chemistry, organometallic chemistry, and organic synthesis.

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