Alpha fluorinated aromatic ketone as nucleophile in asymmetric organocatalytic c n and c c bonds formation reactions 4

It provides a much convenient way to synthesize optically active -amino acid derivatives.1 O R1 R2 N EtO2C CO2Et L-proline 10 mol% MeCN, RT Scheme 3.1 L-proline catalyzed asymmetric -a

Chapter 3

Enantioselective C-N bond formation

reaction catalyzed by chiral bicyclic guanidine

3.1 Introduction

The catalytic, enantioselective, direct C-N bond formation reaction using carbonyl compounds and nitrogen sources, such as azodicarboxylates, is the simplest strategy for the construction of a stereogenic carbon center attached to a nitrogen atom It provides a much convenient way to synthesize optically active

-amino acid derivatives.1

O

R1 R2

N EtO2C

CO2Et

L-proline (10 mol%) MeCN, RT

Scheme 3.1 L-proline catalyzed asymmetric -amination of aliphatic ketones The direct -amination reaction of aliphatic ketones was developed well under organocatalysis conditions The first catalytic enantioselective direct -amination reaction of ketones was presented by Jørgensen and his coworkers in 2002.2 The direct -amination of the various aliphatic ketones 83 (R1 = alkyl) by diethyl azodicarboxylate (DEAD) was carried out in the presence of L-proline with

excellent enantioselectivities (85-major: up to 99% ee), and the reaction was

highly regioselective as the -amination took place at the highest substituted carbon atoms The -hydrazino ketone 86 derived from cyclohexanone was

obtained in good yield and with 84% ee (Scheme 3.1)

O

N N EtO2C

CO2Et

88 (10 mol%)

p-TSA (40 mol%)

2-PrOH, 40oC 4Å MS, 72 h

O

R1

83g R = F 83h R = Br 83i R = CH3

Scheme 3.2 Direct asymmetric -amination of aryl ketones

In contrast, aromatic ketones are less used as direct nucleophilic donors in the asymmetric organocatalysis due to the difficulty in the formation and poor reactivity of the corresponding enamine intermediates Chen and his co-workers3reported the direct enantioselective -amination reaction of aryl ketones 83g-83i (R1 = Ar) with diethyl azodicarboxylate 87 The chiral primary amine catalyst 88

was suitable for the generation of nucleophilic enamines with aryl ketones

83g-83i (R1 = Ar) in presence of 40 mol% p-toluenesulfonic acid (p-TSA) The

linear aromatic ketones 83a-83k, 83m-83p and fused cyclic aromatic ketone 83l were tolerated in this amination reaction Moreover, the amination products 89

were obtained with high ee values (up to 99% ee), although the yields of all the

entries were only moderate (yields of 89: 39%-77%) Long reaction time (72 h)

and high temperature (40 oC) were required because of the poor reactivity of enamine intermediates of aromatic ketones (Scheme 3.2)

O

N N

R1O

yield: 77-95%; 97-99% ee yield: 92-94%; 87-99% ee

R2CN

Scheme 3.3 Direct asymmetric -amination of -cyanoketones

Recently, Kim and his co-workers4 reported the direct -amination reaction of cyclic and acyclic -cyanoketones 90 catalyzed by bifunctional organocatalyst 17

with azodicarboxylate 10b as the electrophilic nitrogen source (the structure of 17,

see Chapter 1) The desired -aminated products 91 were obtained in good to high

yields, and excellent enantioselectivities (87-99% ee) were observed for all the

entries Actually, the introduction of cyano group to the aromatic ketones reduced the pKa value of -proton and drove enolate formation, which made the aromatic ketones suitable to the organocatalysis (Scheme 3.3)

3.2 Enantioselective amination reaction of -fluorinated aromatic ketones

3.2.1 Synthesis of -fluorinated carbonyl compounds 82m-82t, 99a-99c

and di-3-ethylpentan-3-yl azodicarboxylate 106

The procedure of -fluorinated cyclic aromatic ketones 82a-82l was shown in Chapter 2 (Scheme 2.4 in Page 31) Other types of -fluorinated aromatic ketones

82n-82o was prepared by the modification of reported procedure.5

Scheme 3.4 Synthesis of linear -fluorinated ketones

Linear -fluorinated aromatic ketone 82m was easily prepared according to same procedure as synthesis of 82a (Scheme 3.4 equation 1) For 82n and 82o, the intermediates 94 were obtained by bromonation of starting material 93 catalyzed

by AlCl3, followed by halogen substitution between KF and 94 The linear

-fluorinated aromatic ketones 82n and 82o were achieved with moderate yields

due to the difficulty of chromatography of products and unconsumed starting material (Scheme 3.4 equation 2)

We also prepared some other -fluorinated carbonyl compounds 99a-99c for the initial examination of asymmetric amination reaction.6 From commercially

available starting material 2-fluoro-2-phenylacetic acid 95, ethyl 2-fluoro-2-phenylacetate 99b was obtained by esterification reaction under strong acid catalyzed conditions Starting material 95 could be activated by cyanuric chloride 96 by the conversion of carboxylic acid into more reactive acyl chloride, followed esterification with thiol phenyl to generate 99a 3-(2-Fluoro-2-pheny

lacetyl)oxazolidin-2-one 99c was prepared from 95 via nucleophilic attack of lithium salt of oxazolidin-2-one 98 to in situ generated anhydride between 95 and

pivaloyl chloride 97 at -78 oC (Scheme 3.5)

OH O

concd H2SO4bezene reflux

OEt O F

yield: 47.2%

1 1.1 equiv.

Cl O

95

99b

1.5 equiv Et3N -78oC

2 1.1 equiv.

HN O O

1.1 equiv n-BuLi

-78oC N O F

99c

O O yield: 42%

1 equiv PhSH

N N N Cl

yield: 48%

Scheme 3.5 Synthesis of -fluorinated carbonyl compounds 99a-99c

The new nitrogen source di-3-ethylpentan-3-yl azodicarboxylate 106 was

prepared by five-step synthesis according to the modification procedure of

reported literature.7 The bulkier version of azodicarboxylate,

di-3-ethylpentan-3-yl azodicarboxylate 106, was designed as we are aware that

bicyclic guanidine catalyst responds positively to an increase in steric demand of

the substrate 3-Ethylpentan-3-yl 1H-imidazole-1-carboxylate 102 was

synthesized with 82% yield from the much cheaper starting material

1,1’-carbonyldiimidazole (CDI) 100 and 3-ethylpentan-3-ol 101 Under basic condition, 102 reacted with hydrazine hydrate to give 3-ethylpentan-3-yl hydrazinecarboxylate 103 followed treatment by NaNO2 to generate

3-ethylpentan-3-yl carbonazidate 104 The key intermediate 105 was obtained by the reaction between 104 and 103 using pyridine as solvent After the oxidation

with Br2 in pyridine, the product 106 was obtained as yellow solid (Scheme 3.6)

100:CDI

0.6% KOH toluene

60oC

O N

0oC

103

Py rt

O N H

Et3CO

H N

105

O OCEt3

O N

two steps yield: 46%

Scheme 3.6 Synthesis of di-3-ethylpentan-3-yl azodicarboxylate 106

3.2.2 Initial examination of asymmetric amination reaction with Boc=Boc 10b

Firstly, we carried out asymmetric amination between -fluorinated aromatic

cyclic ketone 82d and azodicarboxylate Boc=Boc 10b in presence of 10 mol% chiral bicyclic guanidine catalyst 25 at room temperature The desired product

-hydrozino--fluorinated aromatic cyclic ketone 107d was obtained with high

yield and 76% ee (Scheme 3.7)

Scheme 3.7 Asymmetric amination reation of -fluorinated aromatic cyclic ketone

Scheme 3.8 Other -fluorinated compounds tested in asymmetric amination

aConversion of corresponding products determined by TLC bChiral HPLC ananlysis for corresponding products

Inspired by this result, other -fluorinated carbonyl compounds were tested under the same reaction conditions (Scheme 3.8) The linear -fluorinated

aromatic ketones 82m-82o showed some reactivity in the asymmetric amination

reaction, the best enantioselectivity was obtained with 60% ee and 80%

conversion when with electron-withdrawing group in the aromatic ring of 82o was

used as nucleophile For -fluorinated carbonyl compounds 99a-99c derived from

2-fluoro-2-phenylacetic acid 95, they were less effective in this reaction

3.2.3 Optimization of asymmetric amination reaction of -fluorinated aromatic

a Isolated yields; b Chiral HPLC analysis

Because of the better results obtained from -fluorinated aromatic cyclic

ketone 82d, we took the reaction as model reaction for the further study

1,5,7-triazabicyclo[4.4.0]dec-1-ene (TBD) was used as catalyst for the achiral version In our optimization studies with -fluorinated aromatic ketone 82d, we screened different solvents for this asymmetric amination reaction at room temperature or lowered temperatures The common solvents gave moderate enationselectivities (Table 3.1, entries 1-4) Lewis base type solvents were found

to be the best solvent for this asymmetric amination reaction (Table 3.1, entries

5-8) The best result obtained was 84% ee in THF at -20 oC (Table 3.1, entry 9)

-Hydrozino--fluorinated aromatic cyclic ketone 108d was obtained in 94% ee

with 86% yield when the novel azodicarboxylate 106 (EocN=NEoc) was used as

the nitrogen source (Table 3.1, entry 10) However, the reaction was carried out at

0 oC (Table 3.1)

3.2.4 The scope of asymmetric amination reation

With the optimal reaction conditions in hand (THF as solvent and reaction temperature less than 0oC), the scope of the direct -amination reaction between

-fluorinated aromatic ketones 82a-82k, 82o and azodicarboxylate 106 was investigated A variety of cyclic ketones 82a-82g with varying substituents on the

aromatic ring was prepared from -tetralone derivatives Excellent yields and

high ee values were achieved irrespective of the electronic nature or positions of

the substituents on the aromatic ring (Scheme 3.9) Substrate 82e bearing two

electron-donating groups underwent direct amination reaction in 94% yield and

95% ee For substrate 82f with a strong electron-withdrawing nitro group at

7-position of aromatic ring, the reaction was complete even at -40 oC with 90% ee

The best enantioselectivity was achieved as 96% ee, when substrate 108b was

used as donor due to its steric effect

X

O

F

N N Eoc

O F N NH Eoc

Eoc +

N N N H

tBu tBu

25 (10 mol%)

82a-82g: X = C

82h-82k: X = O

O F Br

O F TsO

O F Cl

O F

O F

O F

O2N

O F F

O

O F

O

O F

O

O F Cl

O

O F F

O F

108a: yield: 88%; 90% ee 108b: yield: 98%; 96% ee 108c: yield: 90%; 91% ee

108dc : yield: 86%; 94% ee 108e c : yield: 94%; 95% ee 108f d : yield: 96%; 90% ee

108hd : yield: 83%; 92% ee 108i c,e : yield: 90%; 90% ee

aIsolated yields bChiral HPLC ananlysis. cReaction temperature is 0 oC dReaction temperature is -40 oC e20 mol% catalyst was used fReaction temperature was room temperature gDetermined by TLC

Similarly, the -fluorinated 4-chromanones derivatives 82h-82k also reacted

efficiently with azodicarboxylate 106, giving the chiral -hydrozino--fluorinated 4-chromanones derivatives 108h-108k in good yields and enantioselectivies (up

to 92% ee) The chromanone moiety can be found in flavanones and many natural

products and they are important compounds in medicinal and biological chemistry, due to their antitumor and anti-inflammatory properties.8 Other -fluorinated

aromatic ketones (82m, 82o-q) were also examined under the similar conditions The linear substrate 82m was less reactive due to the bulky structure, less than

20% conversion was obtained Moreover, a moderate ee value (40% ee) was

obtained when 82o was used as substrate Therefore, substrates with different size

of ring were tested, but the reactivity was not good for the 7-member ring one

82p The 5-member ring one 82q showed some reactivity although there was only

21% ee (Scheme 3.9).

Figure 3.1 X-ray structure of 108a

The absolute configuration of 108a was determined to be (S) by X-ray

crystallographic ananlysis (Figure 3.1) The stereochemistry of other amination

products (108b~108k) was

3.2.5 Proposed mechanism of asymmetric amination reation

Recently, there was an increased attention for utilizing chiral guanidine molecular as Brønsted base catalyst The guanidinium intermediate was formed

by abstracting one proton from the substrate, which could contribute to the stabilization of anionic reaction intermediates through electrostatic interaction and recognize at the active site through hydrogen bonding.9

N N N

Nu E

R3

N N N

Figure 3.2 Previously proposed mechanisms of guanidine

There were two previously proposed mechanisms for guanidine catalyzed addition reaction (a) guanidine molecular act as a dual hydrogen bond donor to form a complex with the deprotonated substrate to attack the electrophile directly; (b) the hydrogen bond formation with the substrate as well as the electrophile to generate a pre-transition-state intermolecular complex (Figure 3.2)

Our group reported two crystal structures of guanidine salt: guanidinium

chloride (Figure 3.3) and guanidinium chloride mono hydrate (Figure 3.4) These experimental details supported the model of bifunctional activation between the guanidine catalyst and substrates.10

N

N N

O H H Cl

Figure 3.4 X-ray structure of guanidinium chloride mono hydrate

The bifunctional mode of the guanidine catalyst was also demonstrated in asymmetric Michael reaction by DFT calculations.11 The Michael reaction was carried out between -fluoro-β-ketoesters 9 and N-substituted maleimides 24

catalyzed by the chiral guanidine catalyst 25 (see, Chapter 1 Scheme 1.8) There

were two possible structures for the pretransition-state complex: face-on or side-on The side-on TS was strongly preferred over the face-on TS because of the

stronger hydrogen bond associated with the maleimide carbonyl group For the four plausible side-on transition states, the calculated preference for the

(S,R)-stereoisomer is in agreement with the observed high enantioselectivity and

diasteroselectivity Interestingly, only one of the two carbonyl oxygens of the

-fluoro-β-ketoesters formed a hydrogen bond with a guanidinium NH proton in all cases (see, Chapter 1 Figure 1.1)

CO2R

CO2R

N N N H

tBu tBu

N N N

N N N

tBu

tBu

H H

O F

O F

N N N

Figure 3.5 The proposed mechanism of asymmetric -amination

From the above experiments and the previous experimental results obtained, we can postulate some facts about the mechanism of this direct asymmetric amination reaction of -fluorinated aromatic ketones (Figure 3.5) Guanidine catalyst 25 was

basic enough to deprotonate fluorinated ketone 82d to form the ion pair complex

II from intermediate I, which was also supported by the asymmetric H/D

exchange experiments The bifunctional guanidine would activate the azocarboxylate though hydrogen bonding before it approached the si-face of the

enolate (intermediate III) The catalyst would be regenerated after releasing the desired amination product 108d

3.3 Modification of amination products

-Fluoro--amino acid structure A is one kind of special -amino acid in

anticipation of the inherent chemical properties and biological activities caused by the introduction of a fluorine atom However, it is a challenge to achieve this kind

of structure due to the instability

F C

109 was treated with CF3CO2D to cleavage the amino protective group, but the

defluorinated product 113 was formed, presumably via the oxazolone intermediate

112 Therefore, cleavage of the ester group prior to deprotection of the amino

group seemed indispensable to maintain the fluorine atom The N-protected

compound 110 was accomplished smoothly without defluorination When it was

treated with a catalytic amount of CF3CO2D or HF in CDCl3, one of the two

carboxylates was cleaved easily to form the unstable intermediate 111 However, prolonged exposure of compound 111 to an excess of HF in CDCl3, defluorination

occurred via N-carboxyimine structure and leaded to decomposed product

118

Scheme 3.11 Dehydrofluorination of 109 under neutral conditions

In considering unfavorable acidic conditions, they tried neutral conditions for