Chapter Chapter Introduction Chapter 1.1 Tandem conjugate addition-elimination (CA-E) reactions The SN2′ reaction (1) and the tandem conjugate addition-elimination reaction (2) which yields SN2′ type product are not often distinguished from one another (Scheme 1.1). Tandem conjugate addition-elimination (CA-E) reaction is the in situ addition of a nucleophile to an α,β-unsaturated compound followed by the elimination of a good leaving group (LG) to yield the SN2′ type product. Tandem CA-E reaction is fundamentally different from SN2′ reaction in that the two reactions proceed via different mechanisms. The substrates of tandem CA-E reactions typically consist of α,βunsaturated systems which are not essential to the SN2′ reaction. To the best of our knowledge, the tandem CA-E reaction is not widely studied. There are few reported examples of tandem CA-E reactions, especially asymmetric versions. In this chapter, we will review various tandem CA-E reactions or SN2′ type reactions. R LG R LG Nu Nu (1) R Nu Nu R' O Nu R LG R' O (2) R R' O Scheme 1.1 SN2′ reaction and tandem conjugate addition-elimination (CA-E) reaction. Morita-Baylis-Hillman reaction has been regarded as a useful carbon carbon bond forming reaction because it produces multi-functionalized molecules like α-methylene βcarbonyl compounds. The products of the Morita-Baylis-Hillman reaction, also known as MBH adducts, contain a minimum of three functional groups: hydroxyl, olefin, and electron-withdrawing groups such as ester, ketone, and so forth.1 Thus, the MBH adducts D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103, 811-891. Chapter are synthetically very useful in various transformations including the synthesis of medicinally relevant compounds as well as complex natural products.2 MBH allylic bromides, which derived from MBH adducts through a single transformation,3 have been well developed for construction of various kinds of molecules. Basavaiah and co-workers have developed a novel SN2′ type addition of hydride anion onto MBH allylic bromides in an aqueous medium.4 This reaction is synthetically useful for its broad substrate scope and environmental friendly conditions. Similar strategy was utilized in the preparation of functionalized 1,4-pentadienes from MBH allylic bromides (Scheme 1.2)5. DABCO was proved to be a good promoter for both reactions. R CO 2Me Br R = aryl, alkyl Ar DABCO THF/H 2O (1:1) rt, 15 NaBH N CO2 Me R rt, 15 Br N DABCO MeO 2C 72-90% Ar CO 2Me CN + Br CO 2Me R CN rt, 7days 37-67% Scheme 1.2 Reaction of MBH allylic bromides promoted by DABCO. Recently, Lee and co-workers reported that amine nucleophiles can attack MBH allylic bromides to yield both SN2 and SN2′ type products (Scheme 1.3). The polarity of the solvents, the basicity and amount of base strongly affect the addition of the amine to G. Masson, C. Housseman and J. Zhu, Angew. Chem. Int. Ed., 2007, 46, 4614-4628. (a) H. M. R. Hoffmann and J. Rabe, J. Org. Chem., 1985, 50, 3849-3859. (b) C. Börner, J. Gimeno, S. Gladiali, J. Goldsmith, D. Ramazzotti and S. Woodward, Chem. Comm., 2000, 2433-2434. (c) L. Fernandes, A. J. Bortoluzzi and M. M. Sá, Tetrahedron, 2004, 60, 9983-9989. D. Basavaiah and N. Kumaragurubaran, Tetrahedron Lett., 2001, 42, 477-479. D. Basavaiah, N. Kumaragurubaran and D. S. Sharada, Tetrahedron Lett., 2001, 42, 85-87. Chapter the allylic bromides. The SN2′ type product can be obtained through a substitution reaction of triethylamine followed by the tandem CA-E process of the amine nucleophile. The SN2 type product could be a valuable intermediate for the synthesis of β-aimno acid. O Ar 0.5 eq Et N, 2eq PhNH Ar NHPh SN2 type product, major hexane O OMe OMe Ph NH O eq Et3 N, 2eq PhNH Br OMe Ar CH2Cl2 SN2' type product, only O O Ar OMe Et N Ph OMe Ar PhNH NH O Ar excess OMe NEt Br SN2' type product Br ammonium salt Scheme 1.3 Lee’s regioselective amination of allylic bromides. A SN2′ type reaction between MBH allylic bromides and carbon nucleophiles was achieved by using DABCO as the promoter (Scheme 1.4). The product could be converted to 2-amino-2,3-dihydrobenzofurans or fully substituted furans via intramolecular Friedel-Crafts type cyclization followed by aromatization process. Ar CO 2Me Br 1. DABCO O2 N aq THF, 20 NO2 Ar CO2Et CO2 Me 2. CO2 Et Scheme 1.4 Reaction between MBH allylic bromides and ethyl nitroacetate. H.-Y. Chen, L. N. Patkar, S.-H. Ueng, C.-C. Lin, A. S.-Y. Lee, Synlett, 2005, 13, 2035-2038. K. Y. Lee, J. Seo and J. N. Kim, Tetrahedron Lett., 2006, 47, 3913-3917. K. Y. Lee, S. Gowrisankar, Y. J. Lee and J. N. Kim, Tetrahedron, 2006, 62, 8798-8804. Chapter In order to develop a practical and efficient method to prepare allylic azide, Sá reported a straightforward nucleophilic substitution of azide anion to MBH allylic bromides (Scheme 1.5).9 The reaction is simple and superior to conventional protocol in terms of reaction rate, workup method and product yield. The mechanistic aspects involved in this transformation remains ambiguous as it could be a direct displacement of azide anion or a conjugate addition-elimination (CA-E) process followed by a [3,3]sigmatropic rearrangement. O O R NaN OMe acetone:H 2O (3:1) 25o C, 10min Br OMe R N3 93-97% Scheme 1.5 Synthesis of allylic azide. In addition to MBH allylic bromide, Orena and co-workers reported a regioselective intramolecular reaction of MBH carbamate10. As shown in Scheme 1.6, when DBU was employed as the catalyst, product A was obtained exclusively. However, the reaction was catalyzed by DABCO in a tandem SN2′- SN2′ mode and yielded product B. These interesting results could be due to the higher nucleophilicity of DABCO with respect to DBU. N CO2Et R O N DBU NHTs A CH2 Cl2 , rt O N H Ts R CO 2Et N NHTs N DABCO CH2 Cl2 , rt R CO 2Et B Scheme 1.6 Reactions of MBH carbamate. 1.2 Asymmetric tandem CA-E reactions M. M. Sá, M. D. Ramos and L. Fernandes, Tetrahedron, 2006, 62, 11652-11656. M. Ciclosi, C. Fava, R. Galeazzi, M. Orena and J. Sepulveda-Arques, Tetrahedron Lett., 2002, 43, 2199-2202. 10 Chapter 1.2.1 Chiral auxiliary strategy An approach to an asymmetric tandem CA-E reaction is the installation of a chiral auxiliary as the leaving group. It was first shown by Fuji et al. that chiral nitro enamines could be used for the asymmetric synthesis of quaternary carbon centers through an addition-elimination process 11 (Scheme 1.7). However, an extra step was needed to prepare the chiral substrate and strong bases such as Lithium diisopropylamide (LDA) were essential to generate the lactone enolates. Low temperature was also required for good enantioselectivity. OMe O O M NO2 N + R1 R = H, CH or C2 H O R2 ether, -78o C R2 NO O R1 30-96% ee R = CH 3, C2 H or CH 2CH=CH2 M + = Li+, Cu+ or Zn 2+ Scheme 1.7 Asymmetric nitroolefination of lactone enolates. Using chiral pyrrolidines as the auxiliary, Tamura showed that it is possible to achieve moderate to high diastereoselectivity with lithium diorganocuprates, leading to optically active 3-substituted 2-exo-methylene-cycloalkanones (Scheme 1.8). 12 The asymmetric synthesis of Clavularin A with high enantio-and diastereoselectivity was also achieved by employing this methodology13. O MeO N n n = 1,2,3 O 1) LiBr, THF, -90 o C to oC + R CuLi-LiBr R = Me, Et, Ph, n Bu, 2) NH Cl or SiO CH=CH n R 90-97% ee 11 K. Fuji, M. Node, H. Nagasawa, Y. Naniwa, T. Taga, K. Machida and G. Snatzke, J. Am. Chem. Soc., 1989, 111, 7921-7925. 12 R. Tamura, K.-i. Watabe, N. Ono, Y. Yamamoto, J. Org. Chem., 1992, 57, 4895-4903. 13 R. Tamura, K.-i. Watabe, N. Ono, Y. Yamamoto, J. Org. Chem., 1993, 58, 4471-4472. Chapter Scheme 1.8 Asymmetric synthesis of 3-substituted 2-exo-methylene-cycloalkanones Although Tamura’s methodology works well with a variety of substrates, the selectivity of the reaction was highly dependent on the types of organometallic nucleophiles and Lewis acids. In addition, the main drawback of this reaction is the preparation of substrates with chiral directing group, which is similar to Fuji’s method. On the contrary, we were interested in developing a fully organocatalytic process for the tandem CA-E reaction. 1.2.2 Organocatalytic asymmetric tandem CA-E reactions or SN2′ type reactions Kim and co-workers firstly disclosed an enantioselective synthesis of MBH alcohols via cinchona alkaloid derivative (DHQD)2PHAL catalyzed kinetic resolution followed by SN2′ type reaction (Scheme 1.9)14. OAc CO2 Me CO2 Me * NR H2 O/THF * NR3 OH (S) NaHCO3 AcO OAc CO2 Me CO2 Me + 13 days, 25%, 92% ee 21%, 80% ee H3 C CH3 N * NR = (DHQD) 2PHAL O N N N O MeO OMe N N Scheme 1.9 Enantioselective synthesis of MBH alcohols. NaHCO3 was used as the water surrogate to hydrolyze the chiral ammonium salt. 14 J. N. Kim, H. J. Lee and J. H. Gong, Tetrahedron Lett., 2002, 43, 9141-9146. Chapter Although up to 92% ee was obtained, the reaction was very slow and low-yielding (2542% yield). Reactions between MBH acetate and phenols or sulfonamides under similar reaction conditions have also been investigated. The enantioselectivities were moderate along with very poor yields. It was reported by Lu and co-workers that Cinchona alkaloids can catalyze the reaction between tert-butyl carbonate of MBH adduct and various pronucleophiles (Scheme 1.10) 15 . Using carbonate as the substrate, tert-butoxide anion was generated after elimination of carbon dioxide. The anion can deprotonate the pronucleophile and generate nucleophilic anion in situ, which makes the reaction catalytical. OH O N OBoc Nu CO2 Me + NuH CO2 Me TQO N toluene, rt O N O CO 2Me 96%, 68% ee MeO 2C O CO 2Me 93%, 72% ee CO2 Me CO 2Me 90%, 51% ee Scheme 1.10 Enantioselective reactions of tert-butyl carbonate of MBH adduct. Allylic amination of MBH acetates with similar strategy using catalytic chiral phosphines also resulted in moderate enantioselectivity (Scheme 1.11)16. A tandem SN2′SN2′ mechanism was proposed and proved by deuterium labeling studies. The key feature of this transformation is the generation of an electrophile-nucleophile ion pair, which 15 16 Y. Du, X. Han and X. Lu, Tetrahedron Lett., 2004, 45, 4967-4971. C.-W. Cho, J.-R. Kong and M. J. Krische, Org. Lett., 2004, 6, 1337-1339. Chapter might suppress direct addition of nucleophile to the less substituted enone moiety of the starting MBH acetate. Nevertheless, this reaction is highly dependent on the basicity difference between the leaving group (OAc-) and the nucleophile anion (Nu-). EWG EWG NuH (200 mol%) AcO R1 Nu PR3 (20 mol%) R2 R1 EWG ElectrophileLeaving Group Ion-Pair EWG PR3 R1 R2 PR3 OAc R2 R1 Nu R2 ElectrophileNucleophile Ion-Pair HOAc + Nu OAc + NuH Cl MeO MeO OAc PPh PPh O CO2Me + O2 N Cl (R)-Cl-MeO-BIPHEP NH (20 mol%) O O N O CO2 Me o THF, 50 C, 62 hrs O2 N 80%, 56% ee Scheme 1.11 Phosphine catalyzed reaction of MBH acetate. A successful tandem CA-E reaction has been developed by Ramachandran for the reaction of various MBH acetates using quaternary Cinchona alkaloids under phase transfer conditions (Scheme 1.12)17. This is a useful method for the synthesis of glutamic acid derivatives. However, this methodology is only applicable to benzophenone imine of glycine tert-butyl ester. 17 P. V. Ramachandran, S. Madhi, L. Bland-Berry, M. V. R. Reddy and M. J. O’Donnell, J. Am. Chem. Soc., 2005, 127, 13450-13451. Chapter (10 mol%) N O OR OAc N O CO2 Me Ph + N Ph t Bu Ar OMe CO 2tBu Ph Br R = allyl Ar = 9-anthracenyl N=CPh2 CsOH H 2O (10 eq) CH2 Cl2 , -78o C 30h, 92%, 92% ee Scheme 1.12 Enantioselective tandem CA-E reaction under PTC conditions. Although a few enantioselective reactions of MBH allylic acetates have been reported, examples of MBH allylic bromides are still limited. It was shown by Basavaish that with equivalents of quinidine, propargyl alcohol can add in a tandem CA-E fashion (Scheme 1.13)18. The salt intermediate was also isolated and characterized via the treatment of MBH allylic bromide with quinidine in CH2Cl2. This is a synthetically useful reaction but enantioselectivities obtained were moderate (25-40%). Ar CO2 Me + Br * Quinidine (NR 3) eq OH CH 2Cl2, rt, 24 hr O Ar CO2 Me 25-40% ee Scheme 1.13 Reaction between MBH allylic bromides and propargyl alcohol. Inspired by these results, we envisage that the MBH allylic bromides could be a useful substrate for an easy introduction of a range of nucleophiles onto the allylic framework. As we know, atom economy, efficiency and selective transformations have become the prime criteria for the development of synthetic reactions. Thus, we are interested in exploring the tandem CA-E reaction of MBH allylic bromides, regio- and stereoselectively using the chiral leaving group strategy. 18 D. Basavaiah, N. Kumaragurubaran, D. S. Sharada and R. M. Reddy, Tetrahedron, 2001, 57, 8167-8172. 10 . Chapter 1 1 Chapter 1 Introduction Chapter 1 2 1. 1 Tandem conjugate addition- elimination (CA-E) reactions The S N 2′ reaction (1) and the tandem conjugate addition- elimination. s R CO 2 Et B N N Scheme 1. 6 Reactions of MBH carbamate. 1. 2 Asymmetric tandem CA-E reactions 9 M. M. Sá, M. D. Ramos and L. Fernandes, Tetrahedron, 2006, 62, 11 652 -11 656. 10 M. Ciclosi, C addition- elimination reaction (2) which yields S N 2′ type product are not often distinguished from one another (Scheme 1. 1). Tandem conjugate addition- elimination (CA-E) reaction is the in situ addition