Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 2

Chapter 2 Chiral bicyclic guanidine-catalyzed enantioselective Phospha-Michael reaction... Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide and 1, 3-diketones, β

Chapter 2 Chiral bicyclic guanidine-catalyzed enantioselective

Phospha-Michael reaction

2.1 Guanidine catalyzed achiral phosphorus-carbon formation reactions

Guanidine (Figure 2.1) is one of the most basic forms of neutral nitrogen compounds and guanidine derivatives are widely used as strong bases in synthetic organic chemistry.1 Due to its high pKaH, guanidine is basic enough to catalyze the Michael addition of a R2P(O)H or (RO)2P(O)H group

N

R3

R1H

R2H

Figure 2.1 General structure of guanidine

3

NMe 2

Me 2 N NH

TMG, 83

Me O

OEt OEt

85 (54%)

Me Me

86

TMG (EtO)2P(O)H

P Me

Me

O

OEt OEt

O

OEt OEt

89a (71%) 89b (51%)

OEt OEt

91

Scheme 2.1 Tetramethylguanidine (TMG) catalyzed the addition of dialkyl

phosphonates to α,β-unsaturated carbonyl compounds

Tetramethylguanidine (TMG, 83) was found to be a good catalyst for the addition

of dialkyl phosphonates to α,β-unsaturated carbonyl compounds2 (Scheme 2.1)

whereas 86 underwent the Michael addition exclusively α,β-Unsaturated esters (88a,b) and nitriles (90) can also be used to give the addition products 89a,b and 91 in

moderate yields

2

P O

PhO PhO

N O

O

Ph (PhO)2P(O)H

N O

O Ph

N H

N N cat.

TBD, 92

94

(PhO)2P(O)H TBD

CN CN

O

PhO PhO

Ph CN CN

98 (88%)

95a

(PhO)2P(O)H TBD

P O

PhO PhO

N P O

PhO PhO

CO2Et N H

CO2Et

100 (86%) 96

Scheme 2.2A TBD catalyzed phospha-Michael reactions of diphenyl phosphonate

Our group reported that 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 92) provided a

mild, rapid and efficient protocol to generate phosphorus–carbon bonds.3 The convenient procedure allowed a series of dialkyl alkylphosphonates (Scheme 2.2A) and trisubstituted phosphine oxides (Scheme 2.2B) to be prepared in high yields (from

70 to 99%) The addition of phosphonates to various activated alkenes, including

maleimide (93a), 2-arylidene malononitrile (94), nitrostyrene (95a) and azodicarboxylate (96) processed smoothly The phosphonates tolerated the

substituents ranging from alkyl to aryl substitutes Cyclic substrates such as

maleimide, as well as linear activated alkenes (102) and 2-cyclopenten-1-one (104a)

were employed in the reaction with diphenyl phosphine oxide to gave good to excellent yields The phosphine oxide was also under further investigation resulted in

a convenient one-pot, three-component reaction containing aldehyde (106) and malononitrile (107) (Scheme 2.2C)

P O

Ph Ph

N O

O

Ph

Ph2P(O)H N

O

O Ph

P O

Ph Ph

Ph O Ph

108c: R = Ph (97%) 108d: R = Cinnamyl (70%) 108e: R = (CH2)3(93%)

107

Scheme 2.2C TBD catalyzed three-component phospha-Michael reactions of

diphenyl phosphine oxide

2.2 Synthesis of chiral bicyclic guanidines and their application in enantioselective reactions

It is anticipated that chiral guanidine derivatives can function as asymmetric

catalysts by utilizing the great basicity of the guanidine group and the special hydrogen bonding pattern of the guanidinium ion This research topic has increasingly attracted great interest and the asymmetric catalytic ability of chiral guanidine or guanidinium salt has been demonstrated in several reactions such as Henry reaction4, Strecker synthesis of α-amino acids5, Michael reaction6, asymmetric silylation of secondary alcohols7, and electrophilic amination8

tBu NHTs

NH2

N H

tBu

NH2

N H

N H

114b (base)

111

Scheme 2.3 Synthesis of symmetrical chiral bicyclic guanidines Reagents and

0 oC to rt; (iv) MeCH, 90 oC, 3 days; (v) Na/NH3, -78 oC; (vi) (MeS)2C=S, MeI/AcOH, MeNO2, reflux; (vii) K2CO3 column

Our group employed the TBD as the template to synthesize a series of chiral

bicyclic guanidines via 6 steps of aziridine-based synthesis and an overall yield of

70% was achieved.9 The synthetic route was modified from Corey’s work.10 Bicyclic

chiral guanidine catalyst 114b was prepared according to the reported procedure as

shown in Scheme 2.3 N-Tosyl aziridine 110 was readily prepared from its

corresponding commercially available α-amino alcohol 109 Triamine unit 112 was easily obtained by treating 110 with NH3 bubbled into its MeOH solution The

nucleophilic attack occurs preferentially at the sterically least hindered carbon atom

The subsequent triamine 113 was prepared by using sodium in liquid ammonia to remove tosyl groups without further purification The crude triamine 113 was then subjected to the final cyclization step, leading to the guanidine 114b .HI in 71% total yield from its amino alcohol The guanidine catalyst was obtained from filtration through K2CO3 column

N H

N N

O OEt

O Et

O S

O S

Scheme 2.4 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide

and 1, 3-diketones, β-keto esters, dithiomalonates

The guanidine 114b was found to be a catalyst for asymmetric Michael reactions

11

ester 115b added to maleimides with high enantioselectivity The Michael adducts

116a-b were obtained in high yields and high ees However, these reactions were slow

and required 20 mol% of catalyst To improve the reaction rate, β-keto thioesters

115c-d and dithiomalonate 115e-f were tested, and the reaction rate was considerably

enhanced Using guanidine 114b as the catalyst, adducts 116c-f were obtained in high

yields and excellent ees with diastereomeric ratios of approximately 1:1 (116c-d) The

catalyst loading of 114b can be decreased to 1 mol% for substrate 115d

O S O

S H

H

R

n

O S O

S H

N H

N N

114b (1-20 mol%)

toluene, -50oC

X O

O

R2O

R1

H

R

O O O

85% yield, 96% ee (20 mol% cat) 86% yield, 90% ee (20 mol% cat)

O S O

S H O

96% yield, 95% ee (10 mol% cat) 91% yield, 97% ee (5 mol% cat)

Scheme 2.5 Chiral bicyclic guanidine catalyzed Michael reactions of cyclic enones

and furanone and 1, 3-diketones, β-keto esters, dithiomalonates

Other cyclic substrates, such as cyclic enones 104a and furanone 104b were also

explored as substrates for this reaction (Scheme 2.5).In general, these reactions were

slow The reactions with various thioesters gave adducts 117a-d in excellent

enantioselectivities and high yields

To extend the scope of this reaction, it was found that ethyl

trans-4-oxo-4-phenylbut-2-enoate 118 was a useful acyclic Michael acceptor (Scheme

2.6) With 5 mol% of guanidine 114b, dialkyl dithiomalonate 115f reacted smoothly

to give adduct 119 in high yields and high ees

Ar O

COR COR

CO2Et

S

O

COR COR

CO2Et

S

R = S

O R

O R

99% yield, 92% ee

N H

N N

O

COR COR

CO2Et

S

99% yield, 94% ee MeO

Scheme 2.6 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl

trans-4-oxo-4-phenylbut-2-enoate and 1, 3-diketones, β-keto esters, dithiomalonates

The guanidine catalyst 114a was also found to be a good catalyst for a highly enantioselective guanidine-catalyzed Diels-Alder reaction between anthrones 120 and

activated olefins (Scheme 2.7).12 High yields and ee values were obtained with various anthrones in combination with maleimides In many examples, the ees were

more than 98% Excellent regioselectivities were also observed when

1,5-dichloro-9-anthrine and 4-(N-methylamino)-9-anthrone were used as the dienes

However, prolonged stirring or treatment of base led to ring-opening products with

significant racemization (121d, 121e)

N O

R5s

s s

OH

N O O Ph s

s

OH

N O O Ph s

s Cl

Cl

121d 87% yield, 99% ee

OH

N O O Et s

s

121e 95% yield, 98% ee

N N N H

O Ph

H

S

N O

O Ph

124c 90% yield 94% ee

Scheme 2.8 Chiral bicyclic guanidine catalyzed Michael reactions of dithranol

When dithranol 122 was employed, the Michael addition adducts 124 were

obtained exclusively Using 10mol% of guanidine, the reaction performed well with maleimides and other activated olefins (Scheme 2.8) Excellent enantioselectivities and regioselectivities were obtained in all examples

2.3 Bicyclic guanidine-catalyzed phospha-Michael enantioselective reactions

The phospha-Michael reactions employing phosphorus nucleophiles such as phosphonates were investigated by many groups,13 especially the excellent research work done by Terada.14 However, to the best of our knowledge, there was no report

on the enantioselective phospha-Michael reactions catalyzed by small molecular using secondary phosphine oxides We aimed to develop an organocatalyst catalyzed phospha-Michael reaction using secondary phosphine oxides

2.3.1 The effects of the catalyst structure on the enantioselectivities

It was found that without any catalyst, the phospha-Michael reaction ofS diphenyl

phosphine oxide 125a and β-nitrostyrene 95a could occur at room temperature (3 h,

50% conversion by NMR) To reduce the effect of this background reaction, the reaction was studied at 0 oC In order to find an efficient catalyst, two categories of catalysts were tested (Table 2.1)

N H

R1N

O2S

Tertiary amine as weak base Hydrogen-bonding donor

Figure 2.2 Chiral pyrrolidinyl sulfonamides (CPS)

Table 2.1 Various chiral catalysts in catalytic phospha-Michael reaction of phosphine

oxide 125a with trans-β-nitro styrene 95a

10 mol% catalyst toluene, 0oC

Ph O Ph

H

1

TsHN

Bn N

Bn Bn

114a

4

N N

114c

a Isolated yield b Chiral HPLC

Chiral pyrrolidinyl sulfonamides (CPS) catalysts were proven to be a good catalyst to promote highly enantioselective tandem conjugate addition-elimination reaction (Figure 2.2).15 This type of catalysts contains a tertiary amine as a weak base, and can activate the phosphine oxides to undergo the phospha-Michael reaction In addition, the acidic –NH group might provide hydrogen-bonding With 10 mol% CPS

catalysts 126, the reactions between phosphine oxide 125 and nitrostyrenes 95a could

not reach complete conversion even after 19 h at 0 oC (Table 2.1, entries 1 and 2) The

products were obtained with 7% and 15% ee, respectively

To improve the conversion of the reaction, the employment of catalysts with stronger basicity was considered A series of synthesized chiral guanidines were examined in the phospha-Michael reaction (Table 2.1 entries 3-5) The guanidines are stronger base than the CPS catalysts so that the guanidine catalysts provided a much higher reaction rate These reactions could be completed within 30 min (expect entry 5)

When the reaction was performed with catalyst 114a, 84% yield and 25% ee were

observed (Table 2.1, entry 3) When the catalyst 114b with more sterically hindered

substituent was employed, the ee was impoved to 40% although longer reaction time

was required (entry 4) The catalyst 114c with a long chain substituent was also

evaluated but only 11% ee and 58% isolated yield was observed (entry 5)

2.3.2 Optimization studies on the reaction of phosphine oxides and nitro

alkenes

With 114b as the optimum catalyst, the reaction was optimized by changing

variables of the reaction conditions Solvent effect was first studied at 0 oC (Table 2.2)

The addition of diphenyl phosphine oxide 125a to β-nitrostyrene 95a was found to proceed smoothly in different types of solvents The product 126a was precipitated

out due to its poor solubility even in polar aprotic solvents like CH3CN and CH2Cl2 (entries 1 and 2) After the indicated reaction time, the reaction mixture was directly

purified via simple filtration through a celite column The products were obtained

with low enantioselectivities (12% and 30%, respectively) The reaction also worked

well in toluene and furnished 82% yield and 40% ee within 30 min (entry 3)

Table 2.2 Solvent effects on the phospha-Michael reaction of phosphine oxides 125a

and trans-β-nitro styrene 95a

(10 mol%) solvent, 0oC

H

N N

Ph P

Ph O Ph

H

114b

Ether type solvents like THF and Et2O gave significant level of

enantioselectivities (Table 2.2, entries 4 and 5) Other ether type solvents (entries 6-10)

such as t-BuOMe (entry 6) were also tested and even lower enantiomeric excess were

observed The reaction in 1,4-dioxane was performed under room temperature due to

its freezing point and 40% ee was observed (entry 10) In summary, the optimum

solvent for the phospha-Michael reaction was determined to be Et2O (53% ee, entry

N H

N N

Ph P

Ph O Ph

H

114b

a Isolated yield via filtration b Chiral HPLC

It was found that the molar ratio of phosphine oxide and nitrostyrene had a

significant influence on the result (Table 2.3) When the nitrostyrene was used as the

limiting reagent, the ee was not determined due to the significant decrease in the

reaction rate and low conversion after 24 hour (entry 1) When the amount of

nitrostyrene was increased from 1:1 (Table 2.2, entry 5) to 1:3 (Table 2.3, entry 2), the

ee was increased to 60% However, when higher amount of nitrostyrene was

employed, the same trend was not observed and the ee decreased to 53% (entry 3 and

4)

2.3.3 Highly enantioselective phospha-Michael reaction between phosphine

oxides and nitrostyrenes catalyzed by chiral bicyclic guanidine

Based on the optimal conditions, a series of diaryl phosphine oxides 125, with a

variety of substituents were investigated (Table 2.4)

Table 2.4 Chiral bicyclic guanidine-catalyzed phospha-Michael reactions with

various diaryl phosphine oxides

N H

N N

R P

R

O R

a Isolated yield via chromatography column; monitored by TLC b Chiral HPLC; ee in

parentheses was obtained after single recrystallization c Reaction performed at -40 oC

d Adduct is a liquid

The diaryl phosphine oxide 125b with electron-withdrawing substitution afford

similar level of ee to the diphenyl phosphine oxide (Table 2.4 entry 2) Longer

reaction time was required when the phosphine oxide 125c with more sterically

hindered substituent was employed However, adduct with 85% yield and only 50%

ee was obtained (entry 3) Although the reaction was performed under -40 oC, reaction

of phosphine oxide 125d with electron-donating group offered a moderate reaction

rate and adduct with 77% yield and 75% ee after 40h was obtained Di(2-naphthyl)-

and di(1-naphthyl)phosphine oxides, 125e and 125f (entries 5 and 6) were also

evaluated; enanioselectivities of 65% and 82% were obtained respectively All

adducts except 126d are crystalline and the optical purity of all adducts were able to

improve to >90% ee after a single recrystallization from MeOH or tBuOMe-DCM

Table 2.5 Chiral bicyclic guanidine-catalyzed phospha-Michael reactions of aryl

N H

N N

R P

R

O R

a Isolated yield b Chiral HPLC; ee in parentheses was obtained after single

recrystallization from hexane and DCM c The absolute configuration was determined

through X-ray crystallographic analysis of 127c d Recrystallization did not work

The reaction between di(1-naphthyl) phosphine oxide 125f and β-nitrostyrene 95a

can be further optimized to 91% ee by decreasing the reaction temperature to -40 oC

(Table 2.5, entry 1) Using the optimized conditions, the addition of 125f to various

aryl nitroalkenes 95 which were derived from aryl aldehydes were investigated

(entries 2–9) Adducts 127a–c were obtained using p-, m- and o-chloro substituted

aryl nitroalkenes (entries 2–4) High yields and high ees for 127a-c were obtained;

showing that substituents pattern on the aryl ring would not affect the