University of Groningen Monodentate secondary phosphine

University of Groningen

Monodentate secondary phosphine oxides (SPO's), synthesis and application in asymmetriccatalysisJiang, Xiaobin

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Chapter 6

Chapter 6

Other applications of secondary phosphine

oxides (SPO’s) in asymmetric catalysis*

This chapter describes the application of SPO’s as ligands in the rhodium- and iridium-catalyzed asymmetric hydrogenation of α- and β-dehydroamino acids and esters, N-acetyl enamides, itaconic acid and its methyl ester and an enol carbamate. In addition, it describes the palladium/SPO-catalyzed asymmetric allylic substitution. Content 6.1 Rhodium-catalyzed asymmetric hydrogenation with SPO ligands 154

6.1.1 Dehydroamino acids and esters 154

6.1.2 Enamides, itaconic acid and its methyl ester 157

6.1.3 An enol carbamate 157

6.2 Palladium- catalyzed asymmetric allylic substitution with SPO’s 160

6.3 Conclusions 163

6.4 Experimental section 163

6.5 References and notes 167 * Part of this chapter has been published, see: Jiang, X.-B; van den Berg, M.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Tetrahedron: Asymm. 2004, 15, 2223.

153

Other applications of secondary phosphine oxides (SPO’s) in asymmetric catalysis

6.1 Rhodium-catalyzed asymmetric hydrogenation with SPO ligands After the successful application of SPO’s as ligands in platinum- catalyzed nitrile hydrolysis (see chapter 4) and iridium catalyzed asymmetric hydrogenation of imines (see chapter 5), it is interesting to examine if SPO’s are suitable as ligands in the rhodium and iridium-catalyzed hydrogenation of other substrates such as α- and β-dehydroamino acids and esters, N-acetyl enamides, itaconic acid and its methyl ester and an enol carbamate. 6.1.1 Dehydroamino acids and esters As asymmetric imine hydrogenation worked quite well with SPO’s as ligands (see chapter 5), it is interesting to explore their application in the asymmetric hydrogenation of several benchmark substrates. In addition to iridium, rhodium complexes were also used. Several α- and β-dehydroamino acids and esters 6.1-6.7 were chosen as substrates in our tests (Figure 6.1).

ORNH

O

O

ORNH

O

O

OHNH

O

HO

R=Me, 6.1; R=H, 6.2 R=Me, 6.3; R=H, 6.4 6.5

ONH

O

OEtONH

O

OEt

6.6 6.7 (mixture of E/Z = 1/4)

Figure 6.1 Structures of α- and β-dehydroamino acids and esters The following conditions were used: [Ir(COD)Cl]2 or Rh(COD)2BF4 as metal precursors, enantiopure SPO’s as ligands (Rh/L = 1/2) (the structures of SPO’s shown in Figure 6.2), DCM, EtOAc or toluene as solvents and 5 bar H2 at RT. The results are shown in table 6.1.

PO

HPO

HPO

H

O

PO

H

L3.4 L3.5 L3.6 L3.7

154

Chapter 6

PO

H PO

HPO

H

PPh2

PO

H

L3.8 L3.9 L3.10 L3.11

O

OP N

H

Ph

PO H

PhPh

OP

O

O

O

O

H

PhPh

PhPh

L3.3 L3.12 L6.1

Figure 6.2 Structures of enantiopure ligands

Table 6.1 The Rh/SPO catalyzed hydrogenation of α- and β-dehydroamino acids and esters a

Entry Substrates Ligands Solvents t (h) Conv. (%) b e.e. (%) b

1 6.1 L3.4 DCM 19 100 25 2 6.1 L3.4 EtOAc 46 100 30

3 c 6.1 L3.12 DCM 69 100 29 4 d 6.1 L3.4 DCM 69 100 27 5 6.2 L3.4 DCM 21 75 -51 6 6.2 L3.4 EtOAc 46 95 28 7 6.3 L3.4 DCM 21 100 39 8 6.3 L3.6 DCM 19 100 30 9 6.4 L3.4 DCM 21 75 -38 10 6.4 L3.4 EtOAc 46 100 53

11 e 6.5 L3.4 Toluene 24 45 29 12 e 6.5 L3.6 Toluene 24 52 22 13 c 6.6 L3.4 DCM 69 100 36 14 6.7 L3.4 DCM 21 41 20

15 c 6.7 L3.4 DCM 69 100 6 (a) General conditions: Rh(COD)2BF4, (R+)-L3.4 or L3.6, M/L=1/2, 2 mol% catalyst loading, 5 bar H2, at RT. (b) Conversions and e.e.’s were determined by chiral GC. (c) 10 bar H2. (d) Ir(COD)2BF4, 10 bar H2. (e) 25 bar H2. From these results, it seems that rhodium or iridium SPO complexes are not very effective in the asymmetric hydrogenation of α- and β-dehydroamino acids and esters as only moderate e.e.’s were obtained. The activity of this system is much lower than that of the standard catalysts such as rhodium-MonoPhos system and long reaction times and higher catalyst loading were needed (table 6.1). The hydrogenation of 6.1 seems not to be sensitive to variation of the conditions. With different metal precursors,

155


solvents or hydrogen pressure, the enantioselectivities are more or less the same (table 6.1, entry 1-4). In DCM, hydrogenation of 6.2 and 6.4 results in the opposite enantiomers as major products compared to the results obtained in EtOAc (table 6.1, entry 5-6, 9-10). We next turned our attention to the asymmetric hydrogenation of sterically hindered tetra-substituted substrates such as 6.8-6.11 (Figure 6.3). They are more difficult to hydrogenate with high e.e.’s.1 The results are shown in table 6.2.

ONH

O

O

ONH

O

OO

ONH

O

O

ONH

O

O

6.8 6.9 6.10 6.11

Figure 6.3 Structures of tetra-substituted α-dehydroamino esters

Table 6.2 Rh/SPO catalyzed hydrogenation of tetra-substituted α-dehydroamino esters a

Entry Substrates Ligands t (h) Conv. (%) b e.e. (%) b

1 6.8 L3.4 69 100 27 2 c 6.8 L3.6 69 75 30 3 6.9 L3.4 69 100 58 4 6.10 L3.4 69 100 15 5 6.10 L3.5 69 100 19 6 d 6.10 L3.5 69 100 7 7 6.11 L3.4 69 100 31 8 e 6.11 L3.4 46 100 -25 9 c 6.11 L3.4 69 100 85 10 c 6.11 L3.6 69 100 81 11 6.11 L3.12 69 100 49

(a) General conditions: Rh(COD)2BF4, M/L=1/2, 2 mol% catalyst loading, 10 bar H2, in DCM at RT. (b) Conversions and e.e.’s were determined by chiral GC. (c) [Ir(COD)Cl]2. (d) Ir(COD)2BF4. (e) 5 bar H2 , EtOAc. Most hydrogenation reactions gave full conversion, but only after long reaction times (Table 6.2). This is presumably due to the increased steric hindrance as compared to the mono α-substituted dehydroamino acid derivatives. The 6-membered ring substituted substrate 6.11 gave the highest e.e. (85%) in our screening with [Ir(COD)Cl]2 and the L3.4 complex in DCM. The ligand L3.6 induced a similar e.e. (table 6.2, entry 9-10). Other ligands led to much lower e.e.’s. The use of Rh(COD)2BF4 as metal precursor, leads to much lower e.e’s (table 6.2, entry 7-8, 11). Interestingly, when the reaction was performed in EtOAc, the major enantiomer of the product had the opposite absolute configuration (table 6.2, entry 8). With Rh(COD)2BF4 and L3.4, substrate 6.9 is converted with higher e.e. than 6.8, 6.10

156

Chapter 6

and 6.11 (table 6.2, entry 1, 3, 4, 7). With L3.12 as ligand, 6.11 is hydrogenated in reasonable e.e., however, for other substrates 6.8-6.10, this ligand leads to much lower e.e.’s (table 6.2, entry 11). The use of Ir(COD)2BF4 gave worse results (table 6.2, entry 6). Compared to recent examples of Zhang about the asymmetric hydrogenation of tetra-substituted dehydroamino acid derivatives (e.e. up to 99%),1a our results (e.e. up to 85%) remain moderate. 6.1.2 N-Acetyl enamide, itaconic acid and its methyl ester Other substrates such as N-acetyl enamide 6.12, itaconic acid 6.13 and itaconic ester 6.14 were tested during our screening under standard conditions. All the results are collected in table 6.3.

Table 6.3 The Rh/L3.4- catalyzed hydrogenation of N-acetyl enamides, itaconic acid and its methyl ester a

NH

O

OR

OR

O

O

6.12 R=H, 6.13; R=Me, 6.14

Entry Substrates Solvents t (h) Conv. (%) b e.e (%) b

1 6.12 EtOAc 46 100 61 2 6.12 DCM 24 100 30 3 6.13 DCM 21 100 45 4 6.13 EtOAc 46 100 7

5 c 6.13 EtOAc 72 95 2 6 6.14 DCM 21 100 36

7 c 6.14 EtOAc 72 50 1 (a) General conditions: Rh(COD)2BF4, (R+)-L 3.4, M/L=1/2, 2 mol% catalyst loading, 5 bar H2, at RT. (b) Conversions and e.e.’s were determined by chiral GC. (c) Ir(COD)2BF4 . Most reactions give full conversion, however, e.e.’s are not satisfactory. The best e.e. we obtained was 61% for the secondary N-acetyl amine derived from 6.12 (table 6.3, entry 1). For other products (and reaction conditions) e.e.’s in the range of 1%-45% were found (table 6.3, entry 2-7). The use of the iridium analogue, Ir(COD)2BF4 as catalyst precursor led to nearly racemic products (table 6.3, entry 5, 7). 6.1.3 An enol carbamate A new method of preparing chiral alcohols could be via the asymmetric hydrogenation of the corresponding enol carbamates. Enol carbamates have not been used until now in asymmetric hydrogenation, only examples about highly enantioselective hydrogenation (e.e. up to 99%) of enol acetates were reported recently.2 In our screening, we found

157


rhodium/SPO complexes to be effective catalysts for this hydrogenation. In contrast, the iridium/SPO complexes that were so successful in the imine hydrogenation are not effective catalysts with these substrates. The conversions in this reaction strongly depends on the purity of enol carbamate 6.15. Traces of impurities were found to deactivate the catalyst system. Substrate 6.15 was prepared by the addition of DMSO anion to acetophenone followed by reaction of the enolate anion with N,N-dimethyl chlorocarbamate at RT. The isolated yield is 45% (Scheme 6.1). The hydrogenation results are shown in table 6.4.

O

Ph

Cl N

OO

O

N

Ph

DMSO + NaH DMSO- Na+

1.)

2.)

45%6.15

Scheme 6.1 Synthesis of enol carbamate 6.15

O N

O

Chiral catalyst

H2

O N

O

6.15 6.15H

Table 6.4 The Rh/L3.4 catalyzed hydrogenation of enol carbamate 6.15 a

Entry Solvents Rh/L H2 (bar) t (h) Conv. (%) b e.e. (%) b

1 EtOAc 1/2 1 64 100 81 2 EtOAc 1/4 1 65 65 84 3 DCM 1/2 5 24 100 32 4 IPA 1/2 1 65 18 70 5 THF 1/2 1 26 3 67 6 Tol 1/2 1 95 40 7 7 EtOAc 1/3 5 44 100 57

8 c EtOAc 1/3 5 44 100 53 9 EtOAc 1/4 5 44 95 61 10 EtOAc 1/8 5 44 89 62

11 d EtOAc 1/3 1.5 45 100 76 12 d EtOAc 1/6 1.5 45 100 76 13 e EtOAc 1/1 1.5 45 81 1 14 f EtOAc 1/1 1.5 45 18 -15 15 g EtOAc 1/2 5 44 34 9

(a) General conditions: Rh(COD)2BF4 / (R+)-L3.4, 2 mol% catalyst loading, at RT. (b) Conversions and e.e.’s were determined by chiral GC. (c) (R+)-L3.6. (d) 40 oC. (e) [Rh(NBD)Cl]2, 40 oC. (f) Ir(COD)2BF4, 40 oC. (g) [Rh(COD)Cl]2.

158

Chapter 6

From these results, it can be concluded that EtOAc is the best solvent and that the combination of Rh(COD)2BF4 and L3.4 is the most effective catalyst for this reaction (table 6.4, entry 1-2, 7-12, also see table 6.5). Interestingly, upon increasing the Rh/L ratio, the e.e. slightly increases (table 6.4, entry 1-2, 8-10). Even with the ratios of 1/6 or 1/8, the reaction still proceeded very well, which might suggest that ligand exchange is relatively fast. The reaction can be accelerated by increasing the temperature or the hydrogen pressure. However, this is accompanied by a decrease in e.e. (table 6.4, entry 11-12). This effect is minor for the temperature change but more severe for the hydrogen pressure. The use of neutral rhodium precursors such as [Rh(COD)Cl2 and [Rh(NBD)Cl]2 leads to a dramatic drop in e.e. (table 6.4, entry 13, 15). With Ir(COD)2BF4 (Ir/L, 1/1), the opposite enantiomer was obtained as the major one, although this reaction showed a poor conversion (table 6.4, entry 14). Upon increase of the Ir/L ratio to 1/2, 1/3 or 1/4, no reactions were observed. The use of [Ir(COD)Cl]2 did not lead to any conversion. Next the effect of the ligand structure (Fig. 6.2) on the rate and the enantioselectivity of this hydrogenation were examined (Table 6.5)

Table 6.5 Ligand effect on the Rh/SPO’s catalyzed hydrogenation of enol carbamate 6.15 a

Entry Ligands Rh/L H2 (bar) t (h) Conv. (%) b e.e. (%) b

1 L3.4 1/1 5 92 75 52 2 L3.4 1/3 5 44 100 57

3 c L3.4 1/2 5 92 25 62 4 d L3.5 1/2 10 69 100 5 5 L3.6 1/3 5 44 100 53 6 L3.7 1/2 2 92 65 2

7 d L3.7 1/2 10 69 82 9 8 L3.8 1/2 5 92 96 3 9 L3.8 1/2 2 92 86 11 10 L3.9 1/2 5 92 43 2 11 L3.9 1/2 2 92 42 1 12 L3.10 1/2 2 92 100 21 13 L3.11 1/2 5 92 65 56 14 L3.3 1/2 1 90 55 56

15 d L3.12 1/2 10 69 100 11 16 e L3.4 + L6.1 1/2 1 72 8 85

17 d,e L3.4 + L6.1 1/2 1 24 10 45 18 d L6.1 1/2 1 24 100 35

(a) General conditions: Rh(COD)2BF4, (R+)-L 3.4, 2 mol% catalyst loading, in EtOAc at RT. (b) Conversions and e.e.’s were determined by chiral GC. (c) With 2 equiv. of pyridine. (d) in DCM. (e) mixture of ligands, L3.4/L6.1=1/1. From these results it is clear that L3.4 is still the best ligand (table 6.5, entry 1-3). Ligands L3.3, L3.6 and L3.11 give comparable results (table 6.5, entry 5, 13-14). The

159


addition of 2 equivalents of pyridine decreases the reactivity dramatically but increases the e.e. somewhat (table 6.5, entry 3). Other ligands such as L3.5, L3.7-L3.10, L3.12 lead to much lower e.e.’s than L3.4 (table 6.5, entry 4, 6-12, 15). As it has already been shown that the hetero-combination of ligand L6.1 with other monodentate phosphoramidites leads to higher enantioselectivities as well as faster reactions than the corresponding “homo-catalysts” in the hydrogenation of dehydroamino acids and esters,3 the combination of ligands L3.4 and L6.1 was tested in our experiments. This does indeed result in a slightly higher e.e. (in EtOAc). However, this reaction is very slow. The use of DCM as solvent leads to a decrease in the e.e. without changing the reaction rate (table 6.5, entry 16,17). An interesting phenomenon in the hydrogenation of enol carbamate 6.15 to 6.15H* is that the e.e. increases with decreasing hydrogen pressure. With the hydrogen pressure as low as 1 bar (H2 balloon), the best result (full conversion, 81% e.e.) is obtained although the reaction is very slow. Increasing the hydrogen pressure to 5 bar, results in a faster reaction, however, the e.e. drops to 57%. This phenomenon has been observed before in other rhodium-catalyzed hydrogenations4 (for details see chapter 1) and is attributed to the fact that the hydrogenation step is now faster than the equilibrium between the two diastereomeric metal-substrate complexes.5 6.2 Palladium- or platinum- catalyzed asymmetric allylic substitution with SPO’s as ligands

Besides asymmetric hydrogenation, other catalytic reactions such as palladium or platinum SPO catalyzed asymmetric allylic substitutions have also been tested. 6 Standard substrate 6.16 was selected as model compound for this procedure. It was easily prepared by reduction of chalcone with NaBH4

7 followed by acetylation with Ac2O in the presence of pyridine (Scheme 6.2).8 Different preformed (see chapter 4) or in situ formed catalysts from palladium or platinum precursors and (R+)-L3.4 were used. The substrate 6.16 was alkylated with dimethyl malonate 6.17 or its sodium salt 6.18 as nucleophiles to obtain the product 6.19 (Scheme 6.2). The results are shown in table 6.6.

9

OAcO

NaBH4

Ac2O, pyridine

91%

1.

2.

6.16

* The hydrogenation products are named by adding H after the name of their substrates. For example, the hydrogenation product of 6.15 was named as 6.15H.

160

Chapter 6

OAcCOOMeMeOOC

3 eqs. of BSA

Catalysts

3 eqs. of 6.17 or 6.18

Cat. NaOAc or KOAc 6.16 6.19

O

MeO

O

OMe

OO

OMeMeO

-

Na+

6.17 6.18

Scheme 6.2 Asymmetric allylic substitution of 6.16 With preformed catalysts C6.1-C6.3, derived from Pt(COD)Cl2 or Pd(COD)Cl2 with L3.4 (Scheme 6.3), no conversions were obtained in most cases, which might be due to the difficulty of the reduction of Pt(II) or Pd(II) to active zero-valent species (table 6.6, entry 1, 3, 6). With the addition of reducing reagent such as NaBH(OMe)3,9a full conversion could be obtained in one case,10 however, the e.e.’s are less than 10% (see table 6.6, entry 8).

OP

MP

O

Clt-Bu

t-Bu

H

H

Ph

PhClt-Bu

PO

HPhM(COD)Cl2

O PM

PO

Cl

t-Bu

t-Bu

HH

Ph

Ph

Cl

3 2:

+ +84%

(R)-(+)-L3.4 M = Pt, C6.1

PM

P

Cl

Cl

MP

PO

t-Bu t-BuO

O

t-Bu

O

t-Bu

HH

Ph

Ph

Ph

Ph

Et3N

80%

M = Pt, C6.2; M = Pd, C6.3

Scheme 6.3 The preformed Pt or Pd catalysts from L3.4

The in situ formed catalysts from Pd(COD)Cl2, Pd(OAc)2 or Pd2(dba)3 with L3.4, also did not perform very well. Some catalyst were completely ineffective, whereas others gave full conversions but with poor e.e’s (around 10%) (see table 6.6, entry 9-12).

161


Table 6.6 Results of allylic substitution of 6.16 to 6.19 with SPO’s as ligands a

Entry Catalysts Nu. NaBH(OMe)3 Conv. (%) b e.e. (%) b

1 c C6.1 6.17 no 0 0 2 C6.1 6.17 yes 40 6 3 C6.1 6.18 no 50 4 4 C6.2 6.17 yes 45 5 5 C6.2 6.18 yes 43 8

6 c C6.3 6.17 no 0 0 7 C6.3 6.17 yes 40 5 8 C6.3 6.18 yes 100 7 9 Pd(COD)Cl2+L3.4 6.17 yes 0 0

10 Pd2(dba)3+L3.4 6.17 no 0 0 11 Pd2(dba)3+L3.4 6.18 no 100 10 12 Pd(OAc)2+L3.4 6.17 yes 0 0 13 Pd(OAc)2+L3.4 6.18 yes 50 8

14 d [Pd(C3H5)Cl]2+L3.4 6.17 no 90 46 15 d [Pd(C3H5)Cl]2+L3.4 6.18 no 95 23 16 d [Pd(C3H5)Cl]2+L3.6 6.17 no 55 35 17 d [Pd(C3H5)Cl]2+L3.12 6.17 no 0 0 18 d [Ir(COD)Cl]2+L3.4 6.18 no 0 0

(a) General conditions: (R)-(+)-L 3.4, M/L = 1/2, 2 mol% catalyst loading, 3 eqs. of 6.17 or 6.18, 3 eqs. of BSA, catalytic KOAc or NaOAc in THF at 60 oC for 67 h [10 mol% NaBH(OMe)3 when it was used]. (b) Conversions were determined by 1H NMR and TLC; the e.e.’s were determined by chiral HPLC (AD, n-heptane/2-propanol, 95/5). (c) RT, 48 h. (d) RT, 72 h. Dai and co-workers recently reported the asymmetric allylic substitution of 6.16 to 6.19 catalyzed by [Pd(C3H5)Cl]2 and L3.4 with 80% e.e. in THF overnight at RT.11 However, we could not fully reproduce this result under the same condition. In our experiments, with [Pd(C3H5)Cl]2 and L3.4, 90% conversion is reached and an e.e. of 46% for 6.19 was found after 3 days at RT (Table 6.6, entry 14). When using nucleophile 6.18 and L3.4, the e.e. drops to 23% (Table 6.6, entry 15). The use of L3.6 as ligand leads to a decrease in the e.e. to 35%. In addition, the reaction rate slows down (Table 6.6, entry 16). Upon use of chiral phosphite L3.12 as ligand no reaction was observed (Table 6.6, entry 17). The use of [Ir(COD)Cl]2 and L3.4 did not give any conversion to the product (Table 6.6, entry 18). In addition to hydrogenation and allylic substitution reaction, catalytic hydroformylation and epoxide ring opening reactions were also briefly tested with SPO’s as ligands (Scheme 6.4). However, no conversions were found in these reactions.

162

Chapter 6

H

O

HOPt(COD)Cl2

+

(R)-(+)-L3.4

Toluene20 bar CO/H2 1/1Pt/L = 1/4 or 1/2

5 mol%X

Cu(OTf)2

OTMSN3

OTMS

N3

5 mol%(R)-(+)-L3.4

Cu/L = 1/2THF, RT

X

Scheme 6.4 Attempted catalytic hydroformylation and epoxide ring opening reactions 6.3 Conclusions It can be concluded from these results that enantiopure secondary phosphine oxides are viable ligands in the asymmetric hydrogenation of a number of substituted olefins. However, the enantioselectivities obtained in the rhodium- or iridium-catalyzed hydrogenation of α- and β-dehydroamino esters and acids (e.e. up to 39%),12 N-acetyl enamides (e.e. up to 61%),13 itaconic acid and its methyl ester (e.e. up to 36%) are much lower than those obtained with MonoPhos and most known bisphosphines (in most cases, e.e.’s up to 99%).12,13 There is one interesting exception: the rhodium-catalyzed asymmetric hydrogenation of enol carbamate 6.15 proceeds with up to 84% e.e., which has no precedent in the literature, although compared to recent examples of enol acetates (e.e. up to 99%), this e.e. remains moderate. The Ir / SPO catalyzed hydrogenation of the branched amino acid precursor 6.11 also gave very promising results (e.e. up to 85%), however still lower than other rhodium catalysts (e.e. up to 99%).14 In the palladium- catalyzed asymmetric allylic substitution, the combination of [Pd(C3H5)Cl]2 and (R)-(+)-L3.4 with dimethyl malonate (6.17) as nucleophile gave a moderate e.e. (46%), however, in slow reaction. Other combinations lead to lower e.e.’s. No reactions were found when SPO’s were used as ligands in catalytic hydroformylation and epoxide ring opening reaction. 6.4 Experimental section General conditions: General conditions see chapter 3, experimental part. The e.e. determination of the hydrogenation products was performed using chiral GC (see table 6.7 for details). Substrate 6.5 was kindly prepared by G. Kruidhof, 6.6-6.7 by D. Pena, 6.8-6.11 by R.

163


Haak, 6.12, 6.15 by M. Van den Berg (all from the University of Groningen). The e.e. of the allylic substitution product 6.21 was determined by chiral HPLC (Daicel, chiralpak AD analytic column, 250 x 4.6 mm i.d.) using n-heptane/2-propanol, 95/5 as solvent. General procedure for asymmetric hydrogenation In order to speed up the screening procedure, we used equipment specially designed for high throughput experimentation (HTE), which are an ordinary autoclave containing 7 vials of 5 ml with stirring bar or the EndeavorTM (8 vials of 10 ml at one time) and a custom made high throughput device (PREMEX) in which 96 high-pressure reactions can be performed simultaneously at DSM. Similar procedures as for asymmetric imine hydrogenation were used. For details see chapter 5, experimental section. The chiral GC conditions for the e.e. determination of the hydrogenation products. The hydrogenation products 6.2H, 6.4H, 6.5H, 6.13H were converted to their corresponding methyl esters by reacting them with 1-2 eqs. of TMSCHN2 in 2 M n-hexane and excess MeOH. The mixtures were then filtered through short pipettes plugged with SiO2 gel, eluted with EtOAc and subjected to GC analysis.

Table 6.7 Chiral GC conditions of the hydrogenation products a Compounds Structure Column Condition t (mins)

6.1H

CP

Chiracel-L-Val

160 oC, 12.5 min, 10 oC/min, 180 oC

tR = 6.7, tS = 7.4,

tSM = 15.4

6.3H

CP

Chiracel-L-Val

110 oC, 15 min, 10

oC/min, 180 oC

tR = 3.4, tS = 3.9,

tSM = 4.2

6.5H

CP

Chiracel-L-Val

90 oC, 15 min, 10

oC/min, 180 oC

t1 = 6.0, t2 = 6.9, tSM = 4.1

6.6H

CP-Chirasil-D

ex-CB

100 oC, 5 min, 10

oC/min, 170 oC

tS = 37.5, tR = 38.1, tSM = 33.1

ONH

O

O

ONH

O

O

ONH

O

HO

ONHAc

OEt

164

Chapter 6

6.7H

CP-Chirasil-

Dex-CB

Same as 6.6H

t1 = 11.8, t2 = 12.0, tSM = 10.7

6.8H

CP

Chiracel-L-Val

140 oC, 16 min, 10

oC/min, 180 oC.

tR = 2.5, tS = 2.7, tSM = 4.5

6.9H

CP

Chiracel-L-Val

Same as 6.8H

t1 = 19.4, t2 = 19.6, tSM = 22.4

6.10H

CP

Chiracel-L-Val

Same as 6.8H

tR = 7.2, tS = 8.1,

tSM = 13.4

6.11H

CP

Chiracel-L-Val

Same as 6.8H

tR = 10.7, tS = 12.3, tSM = 19.2

6.12H

CP-Chirasil-

Dex-CB

140 oC, 45 min

isothermic

t1 = 13.8, t2 = 14.9, tSM = 16.5

6.14H

Chiraldex

G-TA

80 oC, 50 min, 10

oC/min, 150 oC

tR = 19.3, tS = 20.6,

tSM = 29.4

6.15H

CP

Chiracel-L-Val

100 oC, 10 min, 10

oC/min, 180 oC

t1 = 9.8, t2 = 10.1, tSM = 13.2

ONHAc

OEt

NH

O

O

O

NHO

O

OO

NH

O

O

O

NH

O

O

O

NH

O

O

OMe

O

OMe

O

O

N

(a). General conditions: the size of all columns was 25 m × 0.25 mm × 0.25 µm, Tdet. = Tinlet = 250 oC, temperature increase and decrease 10 oC/min.

165


Synthetic procedure to (E)-1,3-diphenyl-2-propenyl acetate (6.16) In a 250 ml round flask, were placed chalcone (10.5 g, 50 mmol and MeOH (100 ml)

and the resulting solution was cooled to 0 oC with ice. To this mixture was added NaBH4 (0.16 mmol, 6 g). After 1 h, TLC showed that the reaction was finished. The mixture was filtered and the solvent was removed to yield the allyl alcohol as colorless sticky oil. The product was used immediately in the

next step without further purification. In another 100 ml round flask, were placed the above alcohol, pyridine (50 ml, 0.62 mol) and DCM (10 ml). To this mixture was added acetic anhydride (25 ml, 0.27 mol) and the solution was allowed to stir overnight at RT. After addition of 50 ml water, extraction with Et2O (3 x 100 ml), washing with saturated aq. CuSO4 solution and brine, the solvent was removed. The residue was further purified by flash column chromatography (SiO2, n-hexane/Et2O, 1/1) to provide 6.16 (11.5 g, 45.6 mmol) as a light yellow sticky oil. Isolated yield 91% over two steps. The spectral data were in accordance with the literature. 1H NMR (CDCl3) 2.12 (s, 3H, CH3), 6.34 (dd, J = 6.5, 15.4 Hz, 1H, =CH), 6.44 (d, J = 7.0 Hz, 1H, CH), 6.63 (d, J = 15.7 Hz, 1H, =CH), 7.20-7.42 (m, 10H). 13C NMR (CDCl3) 168.55, 137.78, 134.70, 131.13, 127.18, 127.13, 126.72, 126.62, 126.04, 125.59, 125.24, 74.69, 19.90. MS (EI+) 253 (M+1), 252 (M), 210, 209, 193, 192 (100%), 191, 165, 115, 105, 91, 77. HRMS (EI+) M+ for C17H16O2, calcd. 252.1150, found 324.1163.

O

O

General procedure for Pd/SPO catalyzed asymmetric allylic substitution reactions In a 25 ml round flask under N2 were placed the palladium precursor (0.01 mmol), the ligand (L3.4, L3.6 or L3.12) (0.022 mmol), 2 mol% catalyst, substrate 6.16 (0.5 mmol, 0.13 g), BSA [N,O-bis(trimethylsilyl) acetamide] (1.5 mmol, 0.31 g), nucleophiles 6.17 (1.5 mmol, 0.2 g), or 6.18 (1.5 mmol, 0.23 g), catalytic NaOAc or KOAc (approx. 10 mg), and 5 ml of dry THF. If necessary, 10 mol% of NaBH(OMe)3 was added. The reaction was monitored by TLC. After stirring at RT or 60 oC for the desired time, the mixture was filtered through a short pipette plugged with SiO2 and washed with 5 ml THF. It was further purified by flash column chromatography [SiO2, petroleum ether (40-60 oC): Et2O, 2:1]. The e.e. of the product 6.19 was determined by chiral HPLC (Daicel, chiralpak AD analytic column, 250 x 4.6 mm i.d.) eluted with n-heptane/ 2-propanol, 95/5. A similar procedure was used with the preformed catalysts C6.1-C6.3 and NaBH(OMe)3. To ensure accurate determination of e.e.’s, the racemate of 6.19 was prepared from Pd(OAc)2 (5.0 mg, 0.022 mmol), PPh3 (12.6 mg, 0.048 mmol), 6.16 (53 mg, 0.21 mmol), 6.18 (60 mg, 0.49 mmol) in 5 ml DCM overnight. The purification procedure was used as above. Isolated yield 87% (59.2 mg, 0.18 mmol).

166

Chapter 6

Dimethyl 2-[(E)-1,3-diphenyl-2-propenyl]malonate (6.19) Prepared from 6.16 (0.13 g, 0.5 mmol) and 6.17 (0.2 g, 0.15 mmol) or 6.18 (0.23 g, 0.15 mmol). It was purified by flash column chromatography [SiO2, petroleum ether (40-60

oC):Et2O, 2:1] to give 6.19 as a colorless oil. Isolated yield 71% (0.12 g, 0.36 mmol). The spectral data were in accordance with the literature. 1H NMR (CDCl3) 3.52 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.96 (d, J = 10.7 Hz, 1H, CH), 4.27 (dd, J = 8.1,

10.8 Hz, 1H, CH), 6.32 (dd, J = 8.1, 15.9 Hz, 1H, =CH), 6.49 (d, J = 15.6 Hz, 1H, =CH), 7.20-7.42 (m, 10H). 13C NMR (CDCl3) 166.70, 166.28, 138.65, 135.30, 130.32, 127.59, 127.22, 126.97, 126.36, 126.08, 125.67, 124.88, 56.14, 51.15, 50.97, 47.70. MS (EI+) 325 (M+1), 324 (M), 292, 264, 260, 232, 205, 204, 193 (100%), 192, 178, 115, 91. HRMS (EI+) M+ for C20H20O4, calcd. 324.1361, found 324.1371.

COOMeMeOOC

The e.e. was determined by chiral HPLC (Daicel, chiralpak AD analytic column, 250 x 4.6 mm i.d.) eluted with n-heptane/2-propanol, 95/5. When using [Pd(C3H5)Cl]2 and L3.4, the e.e. of 6.19 is 46%. t1 = 11.1 min (minor isomer), t2 = 14.2 min (major isomer). 6.5 References and notes 1 For examples of hydrogenation of tetra-substituted dehydroamino acids, see: (a). Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570. (b). Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998, 120, 1635. (c). Burk, M. J.; Feng, S. G.; Gross, M. F.; Tumas, W. J. Am. Chem. Soc. 1995, 117, 8277. (d). Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375. 2 (a). Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.; Paetzold, J.; Jensen, J. F. Org. Lett. 2003, 5, 3099. (b). Wu, S.; Wang, W.; Tang, W.; Lin, M.; Zhang, X. Org. Lett. 2002, 4, 4495. (c). Tang, W.; Liu, D.; Zhang, X. Org. Lett. 2003, 5, 205. (d). Jiang, Q.; Xiao, D.; Zhang, Z.; Ping, C.; Zhang, X. Angew. Chem. Int. Ed. 1999, 38, 516. (e). Burk, M. J. Acc. Chem. Res. 2000, 33, 363. 3 (a). Peña, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Biomol. Chem. 2003, 1, 1087. (b). Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 3111. (c). Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem. Int. Ed. 2003, 42, 790. 4 (a). Ojima, I.; Kogure, T.; Yoda, N. J. Org. Chem. 1980, 45, 4728. (b). Ojima, I.; Kogure, T. Chem. Lett. 1979, 495. (c). Li, R.-X.; Cheng, P.-M.; Li, D.-W.; Chen, H.; Li, X.-J.; Wessman, C.; Wong, N.-B.; Tin, K.-C. J. Mol. Catal. A 2000, 159, 179. (d). Sun, Y.; Landau, R. N.; Wang, J.; LeBlond, C.; Blackmond, D. G. J. Am. Chem. Soc. 1996, 118, 1348. 5 For details of hydrogen pressure effect and mechanism of enantioselective hydrogenation, see chapter 1, paragraph 1.4.

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6 For reviews about palladium catalyzed asymmetric allylic substitution, see: (a). Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymm. 1992, 3, 1089. (b). Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (c). Pfaltz, A.; Lautens, M. in Jacobson, E. N.; Pfaltz, A.; Yamamoto, H. eds., Comprehensive Asymmetric Catalysis, Vol. II, Chapter 24, p 833, 1999, Springer-Verlag, Berlin. 7 (a). Vama, R. S.; Kabalka, G. W. Synth. Commun. 1985, 15, 985. (b). Jayamani, M.; Pant, N.; Ananthan, S.; Narayanan, K.; Pillai, C. N. Tetrahedron 1986, 42, 4325. (c). Aramini, A.; Brinchi, L.; Germani, R.; Savelli, G. Eur. J. Org. Chem. 2000, 9, 1793. 8 (a). Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977, 99, 1649. (b). Aubern, P. R.; MacKenzie, P. B.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2033. (c). Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51, 723. (d). Eiji, I.; Kouji, K.; Hajime, Y.; Nobuko, K.; Yasushi, K. J. Organomet. Chem. 1999, 574, 40. (e). Gotov, B.; Toma, S.; Solcaniova, E.; Cvengros, J. Tetrahedron 2000, 56, 671. (f). Leung, W.; Cosway, S.; Jones, R. H. V.; McCann, H.; Wills, M. J. Chem. Soc., Perkin Trans. I 2001, 20, 2588. 9 (a). Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Humphries, M. E.; Williams, J. M. J. Chem. Eur. J. 2000, 6, 353. (b). Williams, J. M. J. Synlett 1996, 705. (c). Von Matt, P.; Pfaltz, A. Angew. Chem. Int. Ed. 1993, 32, 566. (d). Spintz, J. Helmchen, G. Tetrahedron Lett. 1993, 34, 1769. 10 For the preparation and NMR study of these complexes, see details in chapter 4. 11 Dai, W.-M.; Yeung, K. K. Y.; Leung W. H.; Haynes, R. K. Tetrahedron: Asymm. 2003, 14, 2821. 12 (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539. (b). van den Berg, M.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. (DSM N. V.), WO 0204466, 2002 (c). van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G. Adv. Synth. Catal. 2003, 345, 308. (d). Peña, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552. (e). Zeng, Q.; Liu, H.; Mi, A.; Jiang, Y.; Li, X.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron 2002, 58, 8799. (f). Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159. 13 For a recent review about asymmetric hydrogenation using bis-phosphine ligands, see: Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (a). van den Berg, M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Adv. Synth. Catal. 2002, 344, 1003. (b). Jia, X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 5541. (c). Tang, W.; Chi, Y.; Zhang, X. Org. Lett. 2002, 4, 1695. (d). Li, W.; Zhang, X. J. Org. Chem. 2000, 65, 587. (e). Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem. 1999, 64, 1774. (f). Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679. 14 (a). see ref. 1a, 1d. (b). Ohashi, A.; Imamoto, T. Org. Lett. 2001, 3, 373. (c). Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003, 125, 3534.

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