Organocatalytic reactions of 3 hydroxy 2 pyrone and n arylsulfonyl 3 hydroxy 2 pyridone 1

1.1 BrØnsted-Base Catalyzed Diels-Alder Reactions The Diels-Alder DA reaction is unarguably one of the most powerful bond forming reactions in organic chemistry as it creates as many as

Chapter 1

Introduction

1.1 BrØnsted-Base Catalyzed Diels-Alder Reactions

The Diels-Alder (DA) reaction is unarguably one of the most powerful bond forming reactions in organic chemistry as it creates as many as 4 contiguous chiral centres in one single reaction Since its discovery, it has brought about much advancement in contemporary synthetic organic chemistry.1 The methods whereby DA reactions are traditionally and conventionally carried out included reflux and the use of Lewis acids as catalysts.2 On the other hand, the use of BrØnsted bases as catalysts is a relatively rarer approach.3

Rickborn and Koerner were the first to observe that anthrones can behave as dienes and able to take part in DA reactions with several dienophiles.4 However, it was Kagan and Riant who reported the first enantioselective reaction of anthrones catalyzed

by Cinchona alkaloids (Scheme 1.1).5 Excellent yields were obtained, nevertheless, there

is still much room for improvement in the enantioselectivity

O

N O

O

Me

CHCl3, -50oC HO

N

O Me O

97% yield, 61% ee

2a

quinidine as catalyst

N H N

OMe OH

Scheme 1.1 Diels-Alder reaction of anthrone and N-methyl maleimide catalyzed by

quinidine

Yamamoto et al attempted to improve this anthrone DA reaction using

pyrrolidine derivatives as catalysts Chiral maleimides were used and great results were

pyridyl group proved to be the best catalysts giving an enantiomeric excess of 87% (Scheme 1.3).7 A transition state model between the catalyst and the substrates held together by ionic interactions and hydrogen bondings was also proposed by the authors

O

N O

O

CHCl 3 , rt

major isomer

NH OH

OH

RMe1 H

OH

N O O

R 1

H Me

Scheme 1.2 DA reaction of anthrone and a chiral maleimide catalyzed by C2-symmetric

pyrrolidine diol

Scheme 1.3 DA reaction of anthrone and N-aryl maleimide catalyzed by N-pyridyl

methyl pyrrolidine diol

This anthrone DA reaction was further improved by our group when a BrØnsted– basic bicyclic guanidine was used as the catalyst (Scheme 1.4).8 Good yields of the cycloadducts were obtained and excellent enantioselectivities were achieved The regioselectivity was also excellent The absolute configuration of the compound was determined using X-ray analysis

Scheme 1.4 DA reaction of anthrone and N-aryl maleimide catalyzed by C2-symmetric

bicyclic guanidine

Scheme 1.5 Michael reaction of dithranol and N-benzyl maleimide catalyzed by

C2-symmetric bicyclic guanidine

In addition, it was also found that when the structure of anthrone was slightly altered to include hydroxy groups, i.e dithranol, the reaction between dithranol and maleimides will give a Michael product (Scheme 1.5) No Diels-Alder product was obtained

Okamura et al was the first group to report that BrØnsted bases such as triethylamine (NEt3) can catalyze the Diels-Alder reactions of 3-hydroxy-2-pyrone and electron deficient dienophiles giving cycloadducts in good yields.9 The use of the base varied from a catalytic amount of 0.1 equivalent to 1.0 equivalent and in all cases good yields were obtained (Scheme 1.6)

Scheme 1.6 DA reaction of 3-hydroxy-2-pyrone 1

The enantioselective version was explored by the same group using Cinchona alkaloids

(Figure 1.1).10 Enantiomeric excess as high as 77% was obtained and the selectivity was good

N

N HO

R

R = H, cinchonidine

R = OMe, quinine

R1= R2= H, cinchonine

R1= CH3CO, R2= H

R1= PhCO, R2= H

R1= H, R2= OMe, quinidine

H

N H N

OR 1

R2

Figure 1.1 Cinchona alkaloids used

The best results were obtained when cinchonidine and cinchonine were used and the products were obtained in opposite hands

Following the above results, Deng et al reported the first highly

diastereoselective and enantioselective and DA reactions of 3-hydroxy-2-pyrones (Scheme 1.7).11 The catalysts used were still Cinchona alkaloids However, the structures

were modified and fine tuned to deliver high enantiomeric excesses in the cycloadducts

Scheme 1.7 DA reaction of 1 and α,β-unsaturated ketone esters

N

R2

H N

OH OR1

A : R1= PHN, R 2 = Et

B : R1= Ac, R 2 = -CH=CH 2

C : R1= Bn, R 2 = -CH=CH 2

D : R1= PYR, R 2 = -CH=CH 2

Ph

Ph

Cl 6'

modified

Cinchona

alkaloid scaffold

Cinchona alkaloid derivatives as catalysts

Table 1.1: Diels Alder reaction of 1 and ester catalyzed by Cinchona alkaloid

derivatives

exo isomer

aIn crude reaction mixture bReaction run in Et2O

They also found that the 6’ position hydroxyl group was essential for improving the

catalytic efficiency compared to when natural Cinchona alkaloids were used Several

protecting groups for R1 (PHN, Ac, Bn and PYR) were explored However, the authors

found that the best catalyst was A, in which R1 is the phenanthrene group (PHN) as the

in Et2O improved the diastereoselectivity, as well as the enantiomeric excess (Table 1, entry 5)

In a separate communication, the same authors also reported the use of the modified alkaloid with a primary amine moiety, together with the use of an organic acid

in the Diels-Alder reaction of 1 and α,β-unsaturated ketones (Scheme 1.8).12

Scheme 1.8 DA reaction of 1 catalyzed by a Cinchona alkaloid bearing a primary amine

moiety

The diastereomeric ratio of the products was 80:20 (exo:endo) with the major product (exo) achieving an enantiomeric excess of 98%

Okamura’s group also reported the Diels-Alder reaction of

N-tosyl-3-hydroxy-2-pyridone which is the nitrogen analogue of 3-hydroxy-2-pyrone (Scheme 1.9).13

NTs

OH

O

O

Me

Ts N O

HO

N O

CH2Cl2

(99% yield)

2a

Scheme 1.9 DA reaction of N-tosyl-3-hydroxy-2-pyridone with N-methyl maleimide

Similar to pyrone, triethylamine was used as the promoter for the reaction A single

product was obtained which was determined to be the endo product They reasoned that

the bulky tosyl group might have discouraged the approach to yield the exo product

which resulted in the excellent regioselectivity Another possible reason could be the

bulkier base might have blocked an exo attack as it was observed that a lower endo

selectivity was obtained when a primary amine like tBuNH2 was used as the catalyst Other electron deficient dienophiles (methyl acrylate and methyl vinyl ketone) were also

tested in the DA reactions with N-tosyl-3-hydroxy-2-pyridone and a more sluggish

reaction was observed (Scheme 1.10) The diastereoselectivity was starkly different for the case of acrylate or vinyl ketone as the selectivity was better for the former

Scheme 1.10 Terminal olefins used for the DA reaction with

N-tosyl-3-hydroxy-2-pyridone

Even when 1.0 equivalent of NEt3 was employed as the promoter, the reaction did not proceed to completion

Scheme 1.11 DA reaction of 2(1H)-pyridones with N-phenyl maleimide under neat

conditions

A recent report by Fujita and co-workers made use of 2(1H)-pyridones as dienes for the DA reactions with N-phenyl maleimide under neat conditions.14 Thermal conditions were used and there was no investigation of applying a catalyst to conduct the reaction using milder conditions

With many of the parameters remaining to be changed and tested, there is much room for the improvement and development of this reaction In addition, it was soon discovered that there is much synthetic use for the cycloadducts obtained from the DA

reaction of N-substituted-3-hydroxy-2-pyridone

With all these information, we are sure that there is more research that can be

done on the enantioselective reactions of 3-hydroxy-2-pyrone and

N-substituted-3-hydroxy-2-pyridone

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