Enantioselective tandem conjugate addition elimination reactions 4

Chapter 4 Asymmetric Baylis-Hillman Reactions Promoted by Chiral Imidazolines... chiral phosphine Lewis base catalyst for the Baylis-Hillman reaction of N-sulfonated the reaction betwe

Chapter 4

Asymmetric Baylis-Hillman Reactions Promoted by

Chiral Imidazolines

4.1 Introduction

4.1.1 Baylis-Hillman reaction

The coupling of electrophiles with activated alkenes using tertiary amines or

and atom-economical carbon-carbon bond forming reaction which generates multi-functionalized products such as the α-methylene-β-hydroxycarbonyls This reaction

is notoriously slow; yields are often low and substrate dependent The development of a methodology that is applicable for a range of substrates is much desired

Many versions of the Baylis-Hillman reaction have been developed However, asymmetric examples are still limited hence have received considerable attention in the

Baylis-Hillman reaction between aryl aldehydes and ethyl or methyl vinyl ketones in

utilized as the co-catalyst

ArCHO + R2

O

N

H H

O2N

Ar

OH O

R2 NaBF4, CH3CN, -40oC

Scheme 4.1 Chiral pyrrolizidine catalyzed Baylis-Hillman reaction

1 (a) D Basavaiah, P D Rao and R S Hyma, Tetrahedron, 1996, 52, 8001-8062 ( b) E Ciganek in Organic

Reactions (Ed.: L A Paquette et al.), John Wiley & Sons, Inc: New York, 1997, Vol 51, Chapter 2, 201-350 (c) D

Basavaiah, A J Rao and T Satyanarayana, Chem Rev., 2003, 103, 811-891.

2 (a) P Langer, Angew Chem., 2000, 112, 3177-3180; Angew Chem Int Ed., 2000, 39, 3049-3052 (b) G Masson, C Housseman and J Zhu, Angew Chem Int Ed., 2007, 46, 4614-4628.

3 A G M Barrett, A S Cook and A Kamimura, Chem Comm., 1998, 2533-2534.

Subsequently,β-isocupreidine (β-ICD or TQO),4 a quinidine derivative, was found to

be an effective catalyst for several Baylis-Hillman reactions including that between 1,1,1,3,3,3-hexafluoroisopropyl acrylate and aldehydes or imines (Scheme 4.2) Excellent enantioselectivities were achieved with 10 mol% β-ICD in DMF

O

O

3

CF3

R = aryl or alkyl

R

OH O

O CF3

CF3 31-58%, 91-99% ee N

OH

N O

β-ICD

10 mol%

DMF, -55oC

Ar H

N R

O

O

CF3

CF3

+

DMF, -55 or -30oC

β-ICD (10 mol%) or

O

Ar

NHR O

O CF3

CF3

Ar

NHR O or

up to 99% ee

Scheme 4.2 β-ICD catalyzed reactions

Chiral phosphines have also been observed to be good catalysts for asymmetric

that commercially available chiral phosphine (S)-BINAP could catalyze the reaction between pyrimidine-5-carbaldehyde and acrylates Only moderate enantioselectivities

4 (a) Y Iwabuchi, M Nakatani, N Yokoyama and S Hatakeyama, J Am Chem Soc., 1999, 121, 10219-10220 (b) S Kawahara, A Nakano, T Esumi, Y Iwabuchi and S Hatakeyama, Org Lett., 2003, 5, 3103-3105 (c) M Shi and Y.-M

Xu, Angew Chem., 2002, 114, 4689-4692; Angew Chem Int Ed., 2002, 41, 4507-4510 (d) M Shi and J.-K Jiang, Tetrahedron: Asymmetry, 2002, 13, 1941-1947 (e) M Shi, Y.-M Xu and Y.-L Shi, Chem Eur J., 2005, 11,

1794-1802.

5 (a) T Hayase, T Shibata, K Soai and Y Wakatsuki, Chem Comm., 1998, 1271-1272 (b) M Shi and L.-H Chen,

Chem Comm., 2003, 1310-1311 (c) M Shi, L.-H Chen and C.-Q Li, J Am Chem Soc., 2005, 127, 3790-3800 (d) M Shi and C.-Q Li, Tetrahedron: Asymmetry, 2005, 16, 1385-1391 (d) M Shi, L.-H Chen and W.-D Teng, Adv Synth

& Catal., 2005, 347, 1781-1789 (e) Y.-H Liu, L.-H Chen and M Shi, Adv Synth & Catal., 2006, 348, 973-979 (f) S

I Pereira, J Adrio, A M S Silva and J C Carretero, J Org Chem., 2005, 70, 10175-10177.

chiral phosphine Lewis base catalyst for the Baylis-Hillman reaction of N-sulfonated

the reaction between aldehydes and acrylates, which are known as one of the slowest

15 mol% chiral ferrocenylphosphine

N N

CHO

R1

OR2

O +

R1= H or Me

R2= Me, Et, oriPr

(S)-BINAP

20 mol%

CHCl3, 20oC

N N

R1

OH

OR2 O

8-24%, 9-44% ee

Ar H

N Ts

O +

OH PPh2

10 mol%

THF, -30oC

Ar NHTsO 49-94%, 61-95% ee

O 2 N

H O

O

Fe

Cy2P

PCy2

NMe2 H Ph Ph

NMe2

H

15 mol%

THF, rt O2N

OH O

OBn 78%, 65% ee

Scheme 4.3 Various chiral phosphines catalyzed Baylis-Hillman reactions

to be good catalysts for asymmetric Baylis-Hillman reactions (Figure 4.1) Chen and

co-workers reported that a chiral catalyst formed in situ from camphor-derived ligand and

La(OTf)3 can catalyze the Baylis-Hillman reactions with good ee values in the presence

of DABCO Thiourea was found to be an efficient catalyst for asymmetric

6 K.-S Yang, W D Lee, J.-F Pan and K Chen, J Org Chem., 2003, 68, 915-919.

7 (a) I T Raheem and E N Jacobsen, Adv Synth Catal., 2005, 127, 1701-1708 (b) Y Sohtome, A

Tanatani, Y Hashimoto and K Nagasawa, Tetrahedron Lett., 2004, 45, 5589-5592.

8 J E Imbriglio, M M Vasbinder and S J Miller, Org Lett., 2003, 5, 3741-3743.

Baylis-Hillman reactions as it can activate carbonyl compounds by hydrogen bonding interactions A proline and peptide catalyzed asymmetric Baylis-Hillman reaction between aldehydes and vinyl ketones was disclosed by Miller and co-workers It is worth noting that neither praline nor peptide alone is effective for this reaction in terms of rate

or enantioselectivity

N H

CO2H

BocHN

Peptide O

N N Me Miller's acid-peptide catalyst

OH O

N N

HO O

Chen's chiral ligand

NH NH

S N H S

NH

F3C

CF3

CF3

CF3 Nagasawa's bis-thiourea

N

N H

N H

S

tBu O N Me Bn

HO

tBu tBu Jacobsen's thiourea

Figure 4.1 Acid catalysts for asymmetric Baylis-Hillman reaction

Recent developments include the use of BINOL derivatives as Brønsted acid

(Figure 4.2) Schaus and McDougal have developed a highly enantioselective Baylis-Hillman reaction by several kinds of BINOL-derived Brønsted acids These catalysts were found to be optimum when triethyl phosphine was employed as the nucleophilic co-catalyst Good yields (up to 88%) and excellent enantioselectivities (up to 96%) can be obtained with 10 mol% of the chiral catalyst

9

N T McDougal and S E Schaus, J Am Chem Soc., 2003, 125, 12094-12095.

10 K Matsui, S Takizawa and H Sasai, J Am Chem Soc., 2005, 127, 3680-3681.

11 J Wang, H Li, X Yu, L Zu and W Wang, Org Lett., 2005, 7, 4293-4296.

Sasai’s BINOL-amine catalyst was proved to be efficient for the aza-Baylis-Hillman

reaction between N-tosyl imines and alkyl vinyl ketones Another impressive example of

asymmetric Baylis-Hillman reaction was reported by Wang and co-workers using BINOL derived amine-thiourea as the catalyst

OH OH (R)-BINOL

OH OH X

X

X = Schaus's catalyst

OH OH

N

N

Sasai's BINOL-amine Wang's amine-thiourea

N H N

S N

CF3

Figure 4.2 BINOL derived catalysts

In addition, several asymmetric intramolecular Baylis-Hillman reactions have also

The commonly accepted mechanism of Baylis-Hillman reaction involves the conjugate addition of a nucleophile to generate an enolate, the attack of the enolate onto the aldehyde and subsequent elimination to generate the product However, the effects of

12 (a) P R Krishna, V Kannan and G V M Sharma, J Org Chem., 2004, 69, 6467-6469 (b) C E Aroyan, M M Vasbinder and S J Miller, Org Lett., 2005, 7, 3849-3851 (c) S.-H Chen, B.-C Hong, C.-F Su and S Sarshar, Tetrahedron Lett., 2005, 46, 8899-8903.

13

(a) D Basavaiah, V V L Gowriswari, P K S Sama and P D Rao, Tetrahedron Lett., 1990, 31, 1621-1624 (b) A Gilbert, T W Heritage and N S Isaacs, Tetrahedron: Asymmetry, 1991, 2, 969-972 (c) A A Khan, N D Emslie, S

E Drewes, J S Field and N Ramesar, Chem Ber., 1993, 126, 1477-1480 (d) L J Brzezinski, S Rafel and J W Leahy, J Am Chem Soc., 1997, 119, 4317-4318 (e) P R Krishna, R Sachwani and V Kannan, Chem Comm., 2004, 2580-2581 (f) K.-S Yang and K Chen, Org Lett., 2000, 2, 729-731.

14 B Pégot, G Vo-Thanh, D Gori and A Loupy, Tetrahedron Lett., 2004, 45, 6425-6428.

solvent, the rate determining step, the effects of the pKa of nucleophiles and the role of hydrogen bonding are still under intense investigation for their implication to asymmetric

4.1.2 Chiral imidazolines

Chiral imidazolidinones were developed by MacMillan as highly enantioselective catalysts for a number of reactions including Diels-Alder, 1,3-dipolar cycloaddition and

carboxylic acid This catalyst has been shown to be an effective catalyst for highly

N N

R1

R4

R3

R2 N

N

H

Me Me R

N N H

Me

R CO2H HCl

MacMillan's

imidazolidinones

Jorgensen's imidazoline 1,2-disubstituted-4,5-dihydro-1H-imidazoles

Figure 4.3 Chiral imidazolidiones and chiral imidazolines

Inspired by these examples, we turned our attention to another class of chiral

imidazolines, the 1,2-disubstituted-4,5-dihydro-1H-imidazoles (Figure 4.3) These

15

(a) M L Bode and P T Kaye, Tetrahedron Lett., 1991, 32, 5611-5614 (b) V K Aggarwal, I Emme and S Y Fulford, J Org Chem., 2003, 68, 692-700 (c) K E Price, S J Broadwater, B J Walker and D T McQuade, J Org Chem., 2005, 70, 3980-3987 (d) K E Price, S J Broadwater, H M Jung and D T McQuade, Org Lett., 2005, 7, 147-150 (e) V K Aggarwal, S Y Fulford and G C Lloyd-Jones, Angew Chem., 2005, 117, 1734-1736; Angew Chem Int Ed., 2005, 44, 1706-1708 (f) P Buskens, J Klankermayer and W Leitner, J Am Chem Soc., 2005, 127,

16762-16763.

16 (a) S A Frank, D J Mergott and W R Roush, J Am Chem Soc., 2002, 124, 2404-2405 (b) Y Matsuya, K Hayashi and H Nemoto, J Am Chem Soc., 2003, 125, 646-647 (c) C A Evans and S J Miller, J Am Chem Soc.,

2003, 125, 12394-12395 (d) M E Krafft and T F N Haxell, J Am Chem Soc., 2005, 127, 10168-10169.

17

(a) K A Ahrendt, C J Borths and D W C MacMillan, J Am Chem Soc., 2000, 122, 4243-4244 (b) W S Jen, J

J M Wiener and D W C MacMillan, J Am Chem Soc., 2000, 122, 9874-9875 (c) N A Paras and D W C MacMillan, J Am Chem Soc., 2001, 123, 4370-4371.

18 (a) N Halland, R G Hazell and K A Jørgensen, J Org Chem., 2002, 67, 8331-8338 (b) N Halland, P S Aburel and K A Jørgensen, Angew Chem., 2003, 115, 685-689; Angew Chem Int Ed., 2003, 42, 661-665 (c) N Halland, T Hansen and K A Jørgensen, Angew Chem., 2003, 115, 5105-5107; Angew Chem Int Ed., 2003, 42, 4955-4957.

imidazolines have been developed as possible ligands for enantioselective metal

electronic properties with various 2-substitutents make them appealing The

4,5-dihydro-1H-imidazole is also a privileged structure in which many derivatives exhibit

sulfonated analogue of 4,5-dihydro-1H-imidazole was found to act as a nucleophilic

4.2 Baylis-Hillman reactions promoted by Chiral imidazolines

4.2.1 Chiral imidazoline promoted reaction between various aldehydes and acrylates Chiral imidazoline 53a was readily prepared from the corresponding β-amino alcohol

OH

NH2 Ph Cl

NH Ph

N +

MeOH,Et3N

rt, 1h

1 SOCl2, reflux

Et2O, Et3N

rt, 2days

NH2

Ph 72.3%yield two steps

2.

53a

Scheme 4.4 Synthesis of 53a

We envisioned that 53a might be able to catalyze the Baylis-Hillman reaction

between aldehydes and acrylates as it contains nucleophilic amines As far as we know, few examples of the asymmetric Baylis-Hilman reaction between aldehydes and

19

(a) F Menges, M Neuburger and A Pfaltz, Org Lett., 2002, 4, 4713-4716 (b) A J Davenport, D L Davies, J Fawcett and D R Russell, J Chem Soc., Perkin Trans 1, 2001, 13, 1500-1503.

20

N A Boland, M Casey, S J Hynes, J W Matthews and M P Smyth, J Org Chem., 2002, 67, 3919-3922.

21 V Sharma and J J Tepe, Org Lett., 2005, 7, 5091-5094.

22 A Weatherwax, C J Abraham and T Lectka, Org Lett., 2005, 7, 3461-3463.

unactivated acrylates have been reported5a, 5e, 6 and this reaction is recognized to be one of the slowest due to its combination of substrates

Table 4.1 Reaction of various aldehydes and acrylates in the presence of imidazoline 53a

H

O

2 O

neat, r.t.

N N Ph

OR 2

53a

56

1 eq.

1

Time

2c

It was found that the reaction between 4-nitrobenzaldehyde and methyl acrylate was

catalyzed, albeit slowly, by 10 mol% of imidazoline 53a The product 56a was obtained

in 51% enantiomeric excess, giving an isolated yield of 21% after 14 days when no solvent was used When a series of solvents such as THF, CH3CN, DMSO, MeOH and

the yield and enantiomeric excess with respect to neat conditions However, when toluene

was used, there was a slight improvement in enantioselectivity while the reaction rate decreased The use of the microwave technique or high pressure did not improve the enantioselectivity or conversion of this reaction The addition of hydrogen bonding donors as additives such as thioureas and phenols or changes to the temperature of the reaction, both increasing and decreasing, also did not improve the reaction

In order to make the reaction useful, one equivalent of chiral imidazoline 53a was

used, which increased the yield of the reaction dramatically to 90% (isolated yield, 100% conversion) The enantiomeric excess was also maintained at a satisfactory level (Table 4.1, entry 1) The use of a stoichiometric amount of the imidazoline did not disadvantage the reaction as it can be easily recovered through a simple acid-base work up for reuse without loss of activity (entry 2) However, the reaction still required a long time to complete Subsequently, we surveyed various aldehydes and acrylates with one

equivalent of the chiral imidazoline 53a under neat conditions We examined tert-butyl

acrylate, n-butyl acrylate (entry 3) and benzyl acrylate (entry 4), which all gave similar levels of enantioselectivity as methyl acrylate Both tert-butyl acrylate and n-butyl

acrylate resulted in much slower reactions while benzyl acrylate allowed the reaction to complete in half the time Using the benzyl acrylate, it was found that the promoter

worked well with electron-deficient aromatic aldehydes (entries 5-8) In general, para and meta substituents led to a slightly better enantioselectivity compared to ortho

substituents Alkyl and aromatic aldehydes with electron donating substituents suffered from a slow rate of reaction

4.2.2 Various chiral imidazolines promoted reaction between 4-nitrobenzaldehyde and methyl acrylate

Table 4.2 The reaction of 4-nitrobenzaldehyde and methyl acrylate in the presence of imidazolines 53b-j

O

H +

O OMe

neat, rt

1 eq.

OMe

53b-j

1c

N N Ph

2

N N Ph

Ph

3

N N Ph

Ph

4

N N Ph Ph

Ph

5

N N Ph

6

N N Ph

7

N N Ph

Ph

N

Entry Promoter (days) Time Yield %a ee %b

N

In order to investigate and understand how various substitutents contribute to the asymmetric induction, we tested various chiral imidazolines (Table 4.2) Modifications at

the C4 position from tert-butyl (53a, Table 4.1, entry 1) to benzyl (53b, Table 4.2, entry

1) and phenyl (53c, Table 4.2, entry 2) decreased the enantioselectivity, showing that a

bulky substituent was necessary for high level of enantioselectivity Next, we found that

the imidazoline 53e, with a trans-diphenyl configuration at C4 and C5, turned out to be a slightly better promoter than 53c The effects of various substitutions at C1 were studied

through making a collection of chiral imidazolines An aliphatic group at the C1 position

was found to be crucial as the presence of a phenyl group (entry 3) resulted in an

ineffective promotor The usefulness of an isopropyl substitution at C1 led us to install

the chiral-methylbenzyl groups (entries 5 and 6) and the methylenediphenyl group (entry 7) The enantioselective improvements by these changes were marginal These results showed that the configuration of the chiral center of the methyl-benzyl group (entries 5 and 6) did not influence the effectiveness of the imidazolines However, we observed that

by increasing the size of the C1-substituent, the rate of reaction was slower The use of

the chiral-methylnaphthyl group (entry 8) gave the best result of 84 % isolated yield and

60 % enantiomeric excess Imidazoline 53i were then used to repeat some experiments