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

Deprotection of the TBS group using the standard protocol of BF3.Et2O in CH2Cl2 gave a 60% overall yield of the N-arylsulfonyl-3-hydroxy-2-pyridone product.. Compared to the literature p

Chapter 3

Reactions of 3-hydroxy-2-pyridone

3-Hydroxy-2-pyridone 4a is a cyclic diene which has the following structure:

Figure 3.1 3-Hydroxy-2-pyridone 4a

The main structural difference in pyrone and pyridone lies mainly in that the latter has a nitrogen atom which has the ability to accommodate one more bond (Figure 3.2) With that the structural variety can be stretched to contain more functional groups, which

in turn have the ability to tune the chemical properties of the diene core Being structurally different, their arrangement in space will be different and their physical properties can differ significantly

Most of the chemistry of 4a can be understood by comparison to the oxygen analogue, 1.1 Earlier on, it was mentioned that 1 can be used as a diene in base-catalyzed

DA reactions Thus it should come as no surprise that 4a can also be used as a diene in Diels-Alder reactions The study of DA reactions of 4a shall occupy a major part of this chapter 4a, like 4-hydroxycoumarin, can also take part in other reactions like Michael

reaction, albeit, to a lesser extent, and to a narrower substrate scope To match as much of

4a’s chemistry to that of 1, the nitrogen atom is usually protected to prevent hydrogen

bonding which may interfere in the course of the reaction

NH O OH

O O OH

vs.

N O OH

R = alkyl, aryl

N O OH carbamate protecting group

R = alkyl, aryl

N O OH sulfonyl protecting group

R = alkyl, aryl

R

O

O R

S O

O R

different groups that can be attached

to nitrogen

Figure 3.2 3-hydroxy-2-pyridone 4a versus 3-hydroxy-2-pyrone 1

Compared to the chemistry of 1, the chemistry of 4a is less documented, partly

due to the tediousness in preparing the compounds and lack of information on varying the substrates conveniently There are only a handful of examples in the literature on

reactions with using 4a as the substrate Interestingly, most of the examples made use of

4a with N-sulfonyl protecting group There is an established synthetic route which puts a

sulfonyl protecting group on the nitrogen of the pyridone (Scheme 3.1) The sulfonyl group is chosen mainly because of its robustness to most acidic and alkaline conditions in the reactions Attempts to put other types of protecting groups on the nitrogen, such as Cbz and Boc, in a bid to vary the chemical reactivity had so far been unsuccessful

OH

OH

TBSCl (1.2 eq.) Imidazole (1.5 eq.)

OTBS OH

n-BuLi (1.5 eq.)

ArSO2Cl (1.2 eq.)

Et2O, 0oC - rt

N H

OTBS O

4b : Ar = 2,4,6-Me3C6H2~ 60% overall yield

4c : Ar = 3,5-Me2C6H4~ 60% overall yield

4d : Ar = 2,3,4,5,6-Me5C6~ 25% overall yield

Scheme 3.1 Synthesis of N-arylsulfonyl-3-hydroxy-2-pyridone.2

The synthesis began with the protection of 2,3-pyridinediol with TBSCl using imidazole as a base in CH2Cl2 (Scheme 3.1) ~80% yield can be obtained with a mono-

protection product Subsequently, using n-BuLi and ArSO2Cl under ethereal conditions, the addition of the sulfonyl group can be performed selectively on nitrogen Deprotection

of the TBS group using the standard protocol of BF3.Et2O in CH2Cl2 gave a 60% overall

yield of the N-arylsulfonyl-3-hydroxy-2-pyridone product

Compared to the literature protocol which used TsCl as the sulfonyl source, the yield obtained here is lower and a likely reason could be that the sulfonyl chlorides used contained a larger aryl group When pentamethylphenyl sulfonyl chloride was used, a lower 25% yield of the final pyridone was obtained Other sulfonyl chlorides which are less bulky can give a yield of around 60% which is still acceptable, giving enough amounts for methodology studies

Vasella and co-workers synthesized 4e (the protecting group was 2-naphthyl

sulfonyl) and it was used in the synthesis of manno-configured isoquinuclidines The

products were tested as glycosidase inhibitors They developed a methodology using two

equivalents of a Cinchona alkaloid to promote the reaction between 4e and methyl

acrylate (Table 3.1).2 The product ratio was determined by analytical HPLC of the crude product The conversion of the pyridone to the product was about 90% Although the amount of promoter applied was quite high, this was one of the few reports where an

asymmetric DA reaction of N-arylsulfonyl-3-hydroxy-2-pyridone was reported

Table 3.1 DA reaction of 4e and methyl acrylate promoted by Cinchona alkaloids

Entry Promoter (eq.) Solvent, temperature and

reaction time

Ratio of (+)-5 /(-)-5

synthesis of oseltamivir phosphate (Tamiflu) using N-nosyl-3-hydroxy-2-pyridone 4f

(Scheme 3.2).3 The pyridone was subjected to base catalyzed DA reaction with ethyl acrylate using aqueous sodium hydroxide A yield of 83% was obtained for the DA product NaBH4 was used to open up the amide linkage Following that, iodate oxidation gave the product as a mixture of the two diastereomers and one enol tautomer Reduction using NaBH4 and removal of the alcohol group by mesylation with MeSO2Cl gave the intermediate product for the synthesis of oseltamivir phosphate The nosyl group could be removed easily using PhSH and K2CO3 The amido group can be reprotected with Boc group with ease Using the product obtained, it could be further manipulated with more transformations till oseltamivir phosphate is obtained The route for the synthesis of oseltamivir phosphate was developed by Corey’s group (Scheme 3.3).4

From the above examples it can be seen that the cycloadducts obtained from the

DA reactions of N-sulfonyl-3-hydroxy-2-pyridone can be of great use in synthetic organic

chemistry With such great interest generated, it is important to explore and develop the

asymmetric reactions of N-sulfonyl-3-hydroxy-2-pyridone

N O

HO

CO2Et

Ns NaBH 4 , THF 77%

XHN

CH2OH OH

X = Ns

X = Boc

X = Boc Corey's intermediate

to synthesis of Tamiflu

unstable mixture

of diastereomers and enol tautomer

Scheme 3.2 Okamura’s route to the synthesis of the intermediate leading to synthesis of

oseltamivir phosphate

Scheme 3.3 Corey’s intermediate to Tamiflu

3.2 Asymmetric reactions of N-arylsulfonyl-3-hydroxy-2-pyridones

As mentioned, using cinchonidine as catalyst, the Diels-Alder reaction of 1 and 2a

can be achieved with an enantiomeric excess as high as 77% (Scheme 3.4).5

Scheme 3.4 DA reaction of 1and 2a

With the additional examples by Okamura and Deng, they demonstrated that a molecule containing a hydrogen-bond donor and an acceptor would be a suitable catalyst

for the DA reactions of 3-hydroxy-2-pyrone 1 With this lead, we began to search for a

suitable catalyst for the DA reactions of N-sulfonyl-3-hydroxy-2-pyridone that can bring

about high diastereoselectivity and enantioselectivity The catalysts that were deemed

suitable for the asymmetric DA reactions of 1 were found to be inadequate to complete

the reactions of N-sulfonyl-3-hydroxy-2-pyridone Thus, a new molecular scaffold for the

catalyst needed to be evaluated

Figure 3.3 The CPS catalysts 3a-d

These chiral pyrrolidinyl sulfonamides (CPS) (Figure 3.3) mentioned in the last

chapter were evaluated for the DA reactions of N-sulfonyl-3-hydroxy-2-pyridone They

contained hydrogen bond donor and acceptor moieties, thus, it was reasoned that they

would be effective as catalysts for the DA reactions of N-sulfonyl-3-hydroxy-2-pyridones

The CPS were applied as catalysts, however, only moderate enantiomeric excesses of

30-40 % were achieved

Table 3.2 Reaction between 4b/4d and N-substituted maleimides catalyzed by CPS

10 mol%

3b or 3d

solvent, temp 20h

N O

HO

N O

O R

SO 2 Ar

SO2Ar

6 2

With the preliminary results obtained using the CPS as catalysts, there is an indication that the main features of the catalyst should be retained, i.e the H-bond donor and acceptor The structural features that provided the ideal steric environment needed alteration and improvision so that the maximum stereoselectivity could be obtained After several rounds of screening for the right molecule (synthesis of the catalysts and applied

in the respective DA reactions), the catalyst of choice was finally found (Scheme 3.5)

Scheme 3.5 Amino indanol from the CPS scaffold

The synthesis of the catalyst is simple and straightforward Refluxing the alcohol with 1,4-dibromobutane with K2CO3 as the base in iso-propanol gave the product

amino-in good yield (Scheme 3.6)

Scheme 3.6 Synthesis of amino indanol catalyst

Other catalysts that are obtained in a similar manner include the following:

Figure 3.4 Amino Indanol Catalysts 8a-d

Initial studies employing the above amino alcohols as catalysts for the Diels-Alder

reactions of 4b and 2b gave only moderate results (Table 3.3, entries 1-4) Good yields of

between 85-95% can be obtained but the enantiomeric excess of the cycloadducts was only about 40-60% However, the enantioselectivity was improved after lowering the temperature to -50oC (Table 3.3, entries 7-9) Using the substrates 4b-d, the enantiomeric

excess can reach 81-93% when the reactions were conducted at -50oC The sulfonyl protecting group on the pyridone was required to be alkyl-substituted phenyl group as this gave a faster reaction rate (tosyl protecting group gave a slower rate of reaction) The

catalyst that gave the best optical purity in the bicycloadduct was 8a, where the amino

and alcohol functional groups are cis to each other The cis 8c and 8d (Table 3.3, entries

3 & 4) gave better enantioselectivity than 8b (Table 3.3, entry 2) However, the enantiomeric induction catalysts 8b-d gave was not as superior as 8a (Table 3.3, compare

entries 1-4)

The DA reaction can be carried out in most common solvents However, the best results were obtained when the reaction was performed in chlorinated solvents such as

Scheme 3.7 DA reaction of 4b-d with 2b

Table 3.3 DA reaction of 4b-d and 2b catalyzed by amino indanol catalysts 8a-d

Entry Catalyst, 8 4 Temp/oC Yield/%a ee/%b

CH2Cl2 and CHCl3 Solvents such as THF gave a lower enantiomeric excess while

non-polar solvents like PhMe gave poor conversion to the product After the optimum

phenyl) on the maleimide was investigated (Figure 3.5) Applying N-ethyl maleimide 2e

or N-benzyl maleimide 2c gave the DA product in 87% and 89% enantiomeric excess

Different N-aryl maleimides were synthesized and applied in the DA reactions and the

products could also be obtained in >90%ee (Figure 3.5, adducts 6d-g) This indicated that

the system could tolerate most structural patterns on the maleimides The results are shown below:

Figure 3.5 DA reaction of 4b and N-substituted maleimide using 8a

Figure 3.6 Working model between the catalyst 8a and pyridone 4b

A model for the interaction between the catalyst 8a and the pyridone 4b is

proposed (Figure 3.6) The amino alcohol can form two hydrogen bondings with the

pyridone as a result of 8a and 4b each has one H-bond donor and one H-bond acceptor

Pi-stacking between the catalyst and the pyridone ring (diene) is also possible This leaves the other face the only available site for bond formation between the diene and the dienophile

There is little literature on the synthesis of derivatives of 3-hydroxy-2-pyridone,

4a Most of them are synthesised for biological purposes and the characterization of the

compounds is not comprehensive As the molecule itself contains more than one functionality, its synthesis can be rather complex The usual protection-deprotection technique is required before different groups can be introduced

It is known that 4a has some aromatic character and bears chemical reactivity that

is similar to phenol.1

With this information, we hypothesized that it may undergo electrophilic

substitution reactions similar to phenol such that derivatives of 4a can be synthesized

Simple halogenation was attempted with 4b 4b is used instead of 4a as the

former does not contain an acidic proton which may interfere with the reaction For the

addition of a chlorine atom to 4b, SO2Cl2 (1.3 eq.) was used in the presence of a catalytic

amount of i-Pr2NH (0.1 eq.) in toluene (Scheme 3.8).6 The reaction was warmed to about

70oC and was found to complete in half an hour For the addition of Br to 4b,

N-bromosuccinimide (NBS) was the reagent of choice (Scheme 3.8) Similarly, a catalytic

amount of i-Pr2NH was required for the smooth addition of Br to the 4-position in CH2Cl2

under ambient conditions.7

Scheme 3.8 Introduction of chlorine and bromine to the 4-position of 4b

Apart from NBS, other reagents attempted for the introduction of halogens into 4b

included ICl, NCS and Br2 but they gave a messy reaction profile and no formation of products was clearly observed

O-allyl phenols are known to undergo Claisen rearrangement when heated or

when a Lewis acid is added Thus, the rearrangement reaction was also attempted with

4b.8

Allyl protection of the OH group of 4b was performed using allyl bromide using

K2CO3 in refluxing MeCN The O-allyl product was then refluxed in PhNMe2 at 190oC and it was observed to yield the Claisen rearrangement product after 30 minutes Only an

ortho- product was isolated and the formation of a para- product was not observed

Further transformation of the 4-allyl product could be done by reducing the terminal olefin group A propyl group was generated without affecting the diene core using Pd/C/H2 hydrogenation (Scheme 3.9)

Scheme 3.9 O-allylation of 4b followed by a Claisen rearrangement

Deng’s group reported the carbon-carbon coupling reaction performed on bromo-3-hydroxy-2-pyrone The Suzuki product was obtained in about 30% yield.9

4-Applying the same procedure with 9b, only a low yield of the coupled product (~10%)

was obtained (Scheme 3.10)

Scheme 3.10 Initial scheme for introducing aryl group at the 4-position using Suzuki

coupling

In addition, the reaction was not entirely reproducible Hence, a better synthetic route was required

Using 9b obtained earlier on, the OH group was protected with TBSCl

Subsequently, the O-protected product was coupled with 4-chloro phenyl boronic acid

using Pd(OAc)2/PCy3 as the catalyst system, as described by Fu.10 The TBS group was desilylated with BF3.Et2O smoothly to give 4-aryl-3-hydroxy-2-pyridone 9e (Scheme

3.11) This improved procedure can deliver a higher yield of the coupled product and it was more reproducible

Scheme 3.11 Suzuki coupling of 9b with aryl boronic acid

2-pyridones

We proceeded to use the N-arylsulfonyl-4-substituted-3-hydroxy-2-pyridones for

DA reactions In every case, a DA product was obtained, showing that the character of the diene was not affected by the substituent on the 4-position After some optimization,

high enantioselectivity could also be obtained for the DA products from

N-arylsulfonyl-4-substituted-3-hydroxy-2-pyridones and various maleimides (Figures 3.7 & 3.8)

Scheme 3.12 DA reaction of 9a-e with N-substituted maleimides

N O

O

O Et

S O O

N O

O O

S O O

N O

O O

S O O

N O

O O

S O O

N O

O

O Et

SOO

N O

O O

S O O

Me

10a, 88% yield, 94% ee 10b, 90% yield, 89% ee 10c, 89% yield, 92% ee

10d, 95% yield, 94% ee 10e, 92% yield, 94% ee 10f, 90% yield, 93% ee

Cl

Figure 3.7 DA reaction of 9a-e and N-substituted maleimides using 8a as the catalyst