Chapter Chapter Tandem Conjugate Addition-Elimination Reaction of Linear Activated Allylic Bromides 52 Chapter 3.1 Tandem CA-E reaction between linear Morita-Baylis-Hillman (MBH) allylic bromides and 1,3-dicarbonyl compounds 3.1.1 Synthesis of substrates Inspired by the results obtained from the tandem CA-E reaction of cyclic MBH allylic bromides, we were keen to examine the reaction of linear substrates. As shown in Scheme 3.1, various MBH allylic bromides were prepared by DABCO promoted Baylis-Hillman reactions followed by bromination with concentrated HBr and H2SO4 (1) or NBS together with dimethyl sulfite (2)2. A wide range of commercially available aldehydes and activated alkenes allowed us to prepare a variety of linear MBH allylic bromides. Subsequently, we subjected these MBH allylic bromides to the tandem CA-E reaction conditions. S,S'-Di-tert-butyl dithiomalonate was firstly investigated as the nucleophile for this reaction. O R OH H COR' + CH 2Cl2 or THF, rt COR' R eq DABCO OH COR' conc. HBr/H2SO4 o R CH2 Cl2 , C-rt COR' (1) R Br (Z) OH COR' R NBS, Me2 S CH2 Cl2 , oC-rt COR' R (2) Br (Z) Scheme 3.1 Synthesis of linear MBH allylic bromides. 3.1.2 Reaction between linear MBH allylic bromides and S,S'-di-tert-butyl dithiomalonate (a) C. Börner, J. Gimeno, S. Gladiali, J. Goldsmith, D. Ramazzotti and S. Woodward, Chem. Comm., 2000, 2433-2434. (b) L. Fernandes, A. J. Bortoluzzi and M. M. Sá, Tetrahedron, 2004, 60, 9983-9989. H. M. R. Hoffmann and J. Rabe, J. Org. Chem., 1985, 50, 3849-3859. 53 Chapter While triethylamine was proved to be inefficient for this reaction, a more nucleophilic base, DABCO was employed as the promoter. The achiral tandem CA-E reaction of various linear MBH allylic bromides 39a-j (Table 3.1) was achieved by using equivalents DABCO (Scheme 3.2). Tandem CA-E product was obtained as a single product. t CO2 Me COStBu CH2Cl2 , rt + R COStBu eq DABCO Br R 39a-j N N BuSOC COSt Bu CO2 Me SN2' type product Scheme 3.2 Achiral tandem CA-E reaction between 39a-j and S,S'-di-tert-butyl dithiomalonate. With the model reaction in hand, we started to investigate the asymmetric tandem CA-E reaction between linear substrates 39a-j and S,S'-di-tert-butyl dithiomalonate (Table 3.1). These reactions were generally slower than those of cyclic substrates. Hence, equivalents chiral promoter was used to enhance the reaction rate. However, when CPS 11h was used as the promoter, two products were detected by 1H NMR though only one spot was observed on TLC. We have also attempted different solvent pairs to develop the TLC, but the separation of the two product spots remained a challenge. The side product was assigned as SN2 type product by 1H NMR analysis. However, the reason for the formation of the SN2 type product in the reaction of linear MBH allylic bromides is unknown. Table 3.1 Effect of different substitutions on the aryl group of MBH allylic bromides. 54 Chapter tBuSOC CO2Me COSt Bu CH3 CN, rt + COSt Bu eq 11h Br R 39a-j N MesO2 S Entry a 39, R NH COStBu CO2 Me CO2 Me R + R SN 2' type product 40a-j COStBu COStBu SN type product Product Time(hr) Yield/%a ee/%b SN2′: SN2 ratioc 1d 39a, H 40a 96 - 67 3:1 39b, 4-NO2 40b 27 47 54 5:1 39c, 4-CN 40c 21 64 39 5:1 39d, 4-CF3 40d 97 82 38 3:1 39e, 4-Cl 40e 24 31 47 2:1 39f, 2-Cl 40f 96 35 47 3:1 39g, 3-Cl 40g 44 36 60 4:1 39h, 3-Br 40h 26 54 47 4:1 39i, 3-NO2 40i 27 36 54 4:1 10 39j, 3-CF3 40j 44 33 60 5:1 b Isolated yield of both SN2′ type and SN2 type products. Determined by chiral HPLC analysis. cDetermined by 1H NMR analysis. dVery poor conversion. As shown in Table 3.1, a general observation of asymmetric tandem CA-E reaction was that the yield was typically low, often in the range of 30-60% and the ratio of SN2’ to SN2 type products can vary from ratios of 5:1 to 2:1. When the aryl group contains no substituent (entry 1), the reaction was extremely slow; and a very small amount of product could be obtained for chiral HPLC analysis. MBH allylic bromides with electron withdrawing groups were relatively more reactive and provided moderate ee values (entries 2-5). It was also found that some allylic bromides with substituents in the meta position of the phenyl ring tend to give better ees (entries 7,8 and 10). However, allylic 55 Chapter bromide 39i with NO2 group in the meta position produced same enantioselectivity as 39b. When the substituent in the meta position was changed from chlorine to a bigger group, bromine, the ee dropped from 60% (entry 7) to 47% (entry 8). CO2 Me + Br COStBu CH CN, rt COStBu no reaction eq 11h 41 Scheme 3.3 Reaction between an alkyl substituted MBH allylic bromide and S,S'-di-tertbutyl dithiomalonate. It was noteworthy that when alkyl MBH allylic bromide 41 was employed as the substrate for tandem CA-E reaction, no product was observed (Scheme 3.3). Therefore, we moved on to synthesize MBH allylic bromides from 4-nitrobenzaldehyde and different activated alkenes. With a variety of commercially available acrylates and vinyl ketones, we tried to vary the activated alkene part of the substrates and test how these substituents affect the tandem CA-E reaction. As shown in Table 3.2, when a phenyl acrylate derived MBH allylic bromide 42a was employed, the enantioselectivity decreased by 23% when compared with 39b though an excellent yield was obtained (entry 1). Other phenyl acrylate derived MBH allylic bromides 42b and 42c were proved to be poor substrates in terms of enantioselectivity. As nitro group could form hydrogen bonding with the CPS promoter, it might unlock the substrate-promoter complex which gives high enantioselectivity. It was also observed that alkyl acrylates derived MBH allylic bromides (entries 4,5 and 7) gave similar levels of enantioselectivities. However, the substrate with a long alkyl chain (entry 6) or electron withdrawing group (entry 8) gave very poor ee values. In order to further explore the substrate scope of the reaction, we attempted several 56 Chapter MBH allylic bromides prepared from vinyl ketones (entries 9-11). It was found these reactions were generally slow and gave poor yields. The best ee (57%) was obtained with 42j which was prepared from ethyl vinyl ketone. Table 3.2 Effects of different substitutions on activated alkene part of MBH allylic bromides.a t COR COStBu CH3 CN, rt + COStBu eq 11h Br O2 N 42, R COSt Bu COR O2 N 42a-k Entry BuSOC 43a-k Product Time(hr) Yield/%b ee/%c 42a, OPh 43a 20 99 31 42b, O-2-NO2Ph 43b 18 79 20 42c, O-3-NO2Ph 43c 11 32 42d, OBn 43d 16 93 40 42e, OCHPh2 43e 27 49 45 42f, OnBu 43f 75 31 42g, OtBu 43g 68 20 38 42h, OCH2CF3 43h 12 43 42i, CH3 43i 27 22 46 10 42j, Et 43j 26 20 57 11 42k, Ph 43k 24 55 48 a The SN2′:SN2 ratio was obtained approximately 5:1 by H NMR analysis. bIsolated yield of both SN2′ type and SN2 type products. cDetermined by chiral HPLC analysis. We have also tested the tandem CA-E reaction between 24b and a bulky dithiomalonate (Scheme 3.4). Nonetheless, only 35% ee was obtained along with poor yield (20%) after 22 hours. Therefore, we proceeded to investigate the reactions promoted by different CPS promoters. 57 Chapter ROC CO2 Me COR CH3 CN, rt COR eq 11h + Br O2N CO2 Me O2 N 39b COR R= S 44 22h, 20%yield, 35%ee Scheme 3.4 CPS 11h promoted reaction between 39b and S,S'-di-tert-octyl dithiomalonate. Table 3.3 Effects of different CPS promotersa. tBuSOC CO 2Me COStBu CH 3CN, rt + COStBu eq promoter Br O 2N O 2N 39b Entry Promoter Bn N NHTs COStBu CO 2Me 40b Time(hr) Yield/%b ee/%c 48 47 48 60 60 48 43 51 11a N NH RO2 S R = 2,4,6-triisopropylpheny 11i N MesO2 S NH 11j OMe a The SN2′: SN2 ratio was determined as 5:1 by 1H NMR analysis. bIsolated yield of both SN2′ type and SN2 type products. cDetermined by chiral HPLC analysis. When CPS 11a was used to promote the reaction between 39b and S,S'-di-tert-butyl dithiomalonate, no enantioselectivity was observed (Table 3.3, entry 1). CPS 11i and 11j could also promote this reaction and gave similar results as 11h. 3.2 Other linear substrates 3.2.1 Reactions of linear substrates derived form Baylis-Hillman allylic alcohol 58 Chapter In addition to MBH allylic bromides, we have prepared other linear substrates and subjected them to the tandem CA-E reaction condition. Investigations of CPS 11h promoted reactions between other linear substrates and 1,3-dicarbonyl compounds were shown in Table 3.5. We envisioned that MBH allylic iodide 453 would be an efficient substrate as a better leaving group may enhance the reaction rate of nucleophilic substitution by CPS promoter. To our surprise, the reaction rate was not improved while the enantioselectivity increased by 8% when compared with its corresponding allylic bromide (entry 1). We suspected that the starting material may decompose during the reaction process, which resulted in the moderate yield. Other two substrates 46 and 47 were also synthesized from MBH allylic alcohol and tested for the reaction with S,S'-di-tert-butyl dithiomalonate (entries 2,3). These two substrates gave similar level of yields and SN2′: SN2 ratio as MBH allylic bromide. However, the enantioselectivities of these two reactions decreased dramatically. A possible explanation to this is that these two substrates may undergo double tandem CA-E process or direct nucleophilic substitution reaction to yield product 40b (Scheme 3.5). Therefore, the complexes formed from substrates and promoters might be different from that of MBH allylic bromides. Table 3.4 11h promoted reaction of other substrates derived from Morita-Baylis-Hillman allylic alcohol. t BuSOC COStBu t substrates 45-47 + COS Bu CH Cl , rt 2 COStBu CO 2Me eq 11h O 2N 40b (a) B. Das, A. Majhi, J. Banerjee, N. Chowdhury and K. Venkateswarlu, Tetrahedron Lett., 2005, 46, 7913-7915. (b) J. Li, X. Wang and Y. Zhang, Synlett, 2005, 6, 1039-1041. 59 Chapter Entry Substrate Time(hr) Yield/%a ee/%b 24 35 62 36 33 15 36 24 30 CO 2Me O 2N 45 I OAc CO 2Me O 2N 46 OBoc CO 2Me O 2N 47 a Isolated yield of both SN2′ type and SN2 type products. bDetermined by chiral HPLC analysis. R 3N OAc O O 2N NR t BuSOC OMe O 2N OMe NR O2 N COStBu O t OMe O 2N H COSt Bu O OAc O OMe COSt Bu NR AcO BuSOC - NR NR AcO COStBu CO 2Me O 2N 40b Scheme 3.5 Formation of 40b via double tandem CA-E process. 3.2.2 Reaction of other linear substrates We have also applied the tandem CA-E reaction condition to other activated allylic bromides such as 48 and 51. Methyl 2-(bromomethyl)acrylate 48 is a commercially available activated allylic bromide. With equivalents CPS 11h, several 1,3-dicarbonyl compounds 49a-d were 60 Chapter used to react with substrate 48 (Table 3.5). It is interesting to note that quaternary carbons could be constructed in one step when 49b-d were used as the donor (entries 2-4). Although these reactions could provide moderate to very high yields, no enantioselectivity was obtained, which indicates that CPS may not be a suitable promoter for this reaction. Table 3.5 11h promoted reaction of 48. CO2Me Br Y CH2 Cl2 , rt Z 49 eq 11h + X 48 Entry Donor X Y CO2 Me Z 50a-d Product Time(hr) Yield/%a ee/%b 50a 22 90 50b 21 88 50c 10 60 50d 23 17 CN 49a CO2Et CN CO2 Et 49b O 49c O a O O 49d Isolated yield. bDetermined by chiral HPLC analysis. In addition to commercially available substrate, we have also synthesized 51 from dimethyl itaconate (Scheme 3.6) and subjected it to the tandem CA-E reaction condition. O OMe MeO Br o O Br O CH2 Cl2 , C-rt MeO OMe Br O Br O Et 3N CH2 Cl2 , rt OMe MeO 51 O Scheme 3.6 Synthesis of 37. 61 Chapter When S,S′-di-tert-butyl dithiomalonate was used to react with 51, no reaction was observed even with more equivalents of CPS promoter. Thus, a less hindered donor, S,S'diethyl dithiomalonate was employed. The reaction gave tandem CA-E product 52 in only 20% yield and 20% ee, indicating that 51 is a less reactive acceptor than MBH allylic bromides for the tandem CA-E reaction (Scheme 3.8). O Br O OMe + MeO 51 O COSEt CH Cl , rt 2 COSEt eq 11h MeO OMe O COSEt 52 21 hrs, 20% yield, 20% ee EtSOC Scheme 3.7 Reaction between 51 and S,S'-diethyl dithiomalonate. In conclusion, in this chapter, we described an asymmetric tandem conjugate addition-elimination (CA-E) reaction between linear Morita-Baylis-Hillman allylic bromides and 1,3-dicarbonyl compounds promoted by chiral pyrrolidinyl sulfonamide (CPS). Generally, moderate enantioselectivities were obtained but the yields were less than satisfactory and the reactions often gave a mixture of SN2′-type and SN2 products. Future work includes improving the reaction rate and enantioselectivity using more efficient promoters. 62 [...]... CH Cl , rt 2 2 COSEt 2 eq 11h MeO OMe O COSEt 52 21 hrs, 20% yield, 20% ee EtSOC Scheme 3. 7 Reaction between 51 and S,S'-diethyl dithiomalonate In conclusion, in this chapter, we described an asymmetric tandem conjugate addition- elimination (CA-E) reaction between linear Morita-Baylis-Hillman allylic bromides and 1 ,3- dicarbonyl compounds promoted by chiral pyrrolidinyl sulfonamide (CPS) Generally, moderate...Chapter 3 When S,S′-di-tert-butyl dithiomalonate was used to react with 51, no reaction was observed even with more equivalents of CPS promoter Thus, a less hindered donor, S,S'diethyl dithiomalonate was employed The reaction gave tandem CA-E product 52 in only 20% yield and 20% ee, indicating that 51 is a less reactive acceptor than MBH allylic bromides for the tandem CA-E reaction (Scheme 3. 8) O Br... allylic bromides and 1 ,3- dicarbonyl compounds promoted by chiral pyrrolidinyl sulfonamide (CPS) Generally, moderate enantioselectivities were obtained but the yields were less than satisfactory and the reactions often gave a mixture of SN2′-type and SN2 products Future work includes improving the reaction rate and enantioselectivity using more efficient promoters 62 . 21 64 39 5:1 4 39 d, 4-CF 3 40d 97 82 38 3: 1 5 39 e, 4-Cl 40e 24 31 47 2:1 6 39 f, 2-Cl 40f 96 35 47 3: 1 7 39 g, 3- Cl 40g 44 36 60 4:1 8 39 h, 3- Br 40h 26 54 47 4:1 9 39 i, 3- NO 2 . 43a 20 99 31 2 42b, O-2-NO 2 Ph 43b 18 79 20 3 42c, O -3- NO 2 Ph 43c 11 32 0 4 42d, OBn 43d 16 93 40 5 42e, OCHPh 2 43e 27 49 45 6 42f, O n Bu 43f 75 31 7 7 42g, O t Bu 43g. Chapter 3 52 Chapter 3 Tandem Conjugate Addition- Elimination Reaction of Linear Activated Allylic Bromides Chapter 3 53 3. 1 Tandem CA-E reaction