Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 3

Chapter 3 Chiral Guanidinium Salt Catalyzed Phospha-Mannich Reactions... This proton catalyst 153 was found to increase the reaction rate of a series of reactions like Diels-Alder react

Chapter 3

Chiral Guanidinium Salt Catalyzed Phospha-Mannich

Reactions

3.1 Hydrogen bond donors catalyzed asymmetric reactions

Electrophilic activation by small-molecule hydrogen bond donors has provided an

important paradigam for design of enantioselective catalysts.1 Salts of organic bases

were shown to be successful in the activation of imines and other anionic

intermediates through hydrogen bonds

Ph Ph

Ph 2BArF-4

O OH H

H

R

152a R = Me 152b R = Et

MeO

OH H

R H

O 151a R = Me 151b R = Et

a 80% yield 151a 15% ee152a 47% ee 151a/152a 1:22

b quant yield 151b 48% ee 152b 7% ee 151b/152b 1:11 149

148

Scheme 3.1 Göbel’s chiral bis(amidinium) salt 148 catalyzed Diels-Alder reaction

Göbel and co-workers2 reported a chiral bis(amidinium) salt 148 catalyzed

Diels-Alder reaction which constituted a key step of the Quinkert-Dane Estrone

Synthesis The hydrogen-bond-mediated association of dienophiles 149 with the

chiral salt 148 accelerated the Diels-Alder reaction with diene

7-methoxy-4-vinyl-1,2-dihydronaphthalene (149) by more than three orders of

magnitude In addition, the chemo-selectivities of the adducts were excellent

(151a:152a = 1:22 and 151b:152b = 1:11, respectively) However, only moderate

The drawback of this type of proton catalyst was that the bisamidine 148 cannot

bind a single carbonyl group by two hydrogen bonds simultaneously because of the

large distance between the amidinium groups To expand the scope of

amidinium-catalyzed reaction, Göbel and co-workers3 reported an easily synthesized

bisamidines 153 derived from malonodinitril This proton catalyst 153 was found to

increase the reaction rate of a series of reactions like Diels-Alder reaction and

Friedel-Crafts reaction (Scheme 3.2) Enantioselectivities, however, remained

constantly low even at low temperature

O +

H N

H N Ph

Ph Ph

Johnston and co-workers reported the use of a chiral proton catalyst 158 to

promote enantioselective direct aza-Herry reaction (Scheme 3.3).4 The catalyst can

tolerate a range of substituents and substitution patterns on several aldimines 159 and

nitroalkanes Nitroacetic acid easters can afford similar results in which anti-addition

products were preferred.5 The catalysts can be easily removed from the final reaction

mixture via a base wash

Scheme 3.3 Johnston’s chiral proton catalyst catalyzed enantioselective direct

aza-Herry reaction

3.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions

The addition of phosphonates to imines (Pudovik reaction or phospha-Mannich

reaction) is a widely utilized method for the formation of P-C bonds However, to best

as secondary phosphine oxides [R2P(O)H] and H-phosphinates [(RO)P(O)HR] for the

addition to imines The only previous report on the preparation of P-chiral

phosphinate esters was through resolution using phosphotriesterase.6 Yuan and

co-workers reported the synthesis of optically pure α-amino-H-phosphinic acids

employing chiral ketimines.7 We aimed to develop an organocatalyst catalyzed

phospha-Mannich reaction using secondary phosphine oxides and H-phosphinates

3.2.1 Synthesis of guanidinium salt 168

2-Chloro-1,3-dimethylimidazolinium chloride 163 was found to form guanidines

easily with appropriate primary amines.8 This type of reaction provided a simple

method to prepare guanidines/guanidinium salts (Scheme 3.4)

NMe MeN

N Me

+

MeN NMe

165 Scheme 3.4 Synthesis of guanidines from DMC 163 and amine

H2N NH2

N

Cl N

Ph Ph

N N

+ +

Scheme 3.5 Synthesis of guanidinium salts

Guanidinium 168 .2HBF4 was prepared from enantiopure diamine 166 and

pyrrolidinium salt 167 in one step with excellent yield (Scheme 3.5) The free base

guanidine 168 was obtained after basifying guanidinium salt 168 .2HBF4 with 6M

NaOH aqueous solution The absence of 19F signal detected in the 19F NMR indicated

the successful basification of 168 .2HBF4

3.2.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions of

phosphine oxides

3.2.2.1 Optimization study of phospha-Mannich reactions of phosphine oxides

Table 3.1 Guanidine- and guanidinium-catalyzed phospha-Mannich reactions

R R O P

R R O

In preliminary studies, it was found that both the guanidinium salt 168 .2HBF4 and

guanidine 168 could catalyze the phospha-Mannich reaction between secondary

phosphine oxides and imines (Table 3.1, entries 1 and 5) It was surprised that the

results in terms of enantioselectivities obtained in the presence of the catalysts

basified from K2CO3 were inconsistent It was proposed that this basification method

offered catalysts carrying uncertain numbers of protons and the number of protons on

the catalyst had a significant influence on the ees This effect was evaluated by

employing catalysts 168 .xHBF4 (x = 0.5, 1, 1.5) prepared purposely These catalysts

168 .xHBF4 (x = 0.5, 1, 1.5) were obtained by mixing different ratio of the free base

168 and 168 .2HBF4 (ratio = 1:3, 1:1, 3:1, respectively) It was discovered the highest

ee was obtained with catalyst 168.HBF4, which carried one single proton (entry 3)

The results obtained with other catalysts dropped dramatically (entries 1, 2, 4 and 5)

N N

N

BF4H

iPr iPr iPr

iPr iPr

BF4H

-iPr iPr iPr iPr

NH2

Figure 3.1 A series of guanidinium salts synthesized as catalysts for

phospha-Mannich reactions

Following the previous studies, a series of guanidinium salts carrying one proton

(Figure 3.1) were synthesized readily from commercially available chiral diamines

and corresponding salts under the same conditions In the case of preparation of 173,

only guanidine salt 174 was obtained rather than 173 .2HBF4 even under hash

conditions (MeCN, reflux) It was likely that the steric effect prevented the formation

of the second guanidine

Table 3.2 The effect of catalyst structure on enantioselectivity

R R O P

R R O

These guanidinium salts were also evaluated in the phospha-Mannich reaction of

phosphine oxides (Table 3.2) Both the guanidinium salt 170 .HBF4 bearing less

sterically hindred group (entry 1) and the guanidinium salt 171 .HBF4 derived from the

dicyclohexyl amine (entry 2) gave poor enantioselectivities At -20 oC, the

guanidinium salt 172 .HBF4 gave good enantiomeric excess but worse than 168 .HBF4

The reaction temperature was another factor which may be considered to increase the

optical purity significantly Fortunately, decreasing the reaction temperature to -50 oC

did not affect the reaction rate much; the reaction catalyzed by 168 .HBF4 at -50 oC

could complete within 14 h and good result was observed (entry 4) It was reported

that different counterions of the chiral salt catalysts could affect the reaction rate and

enantioselectivities.3 In our current research, the guanidinium salts with different

weakly-coordinating anions were tested under -50 oC (entries 5 and 6) It was found

that the ee increased to 92% when -BArF4 (Figure 3.2), the less coordinating anion,

was employed

3.2.2.2 Highly enantioselective phospha-Mannich reaction between phosphine

oxides and imines catalyzed by guanidinium salts

Under the optimum conditions, the phospha-Mannich reaction was investigated

with phosphine oxide 125f and different imines (Table 3.3, entries 1-7) Imines

bearing electron-donating (entry 1) and electron-withdrawing substituents (entry 2)

provided adducts with high ees The reaction time for completed conversion of the

bulky 2-naphthyl imine was also 14h and 92% ee was observed (entry 3)

Heterocyclic imine (entry 4) furnished slightly lower ee Imines derived from

aliphatic aldehydes, such as cyclohexanecarbaldehyde, gave adduct with 70% ee

(entry 5) while imine derived from pivalaldehyde afforded adduct with 91% ee (entry

6) Imine derived from trans-cinnamyl aldehyde also provided 1,2–addition adduct

169h with high ee (entry 7) Diaryl phosphine oxides 125a and 125g carrying phenyl

and ortho-trifluoromethylphenyl groups respectively, afforded adducts with moderate

to good ees (entries 8 and 9) The racemic phosphine oxide 125h added to phenyl

imine to generate two diastereisomers with a diastereisomeric ratio (dr) of 1:1 and

high ees (entry 10)

Table 3.3 Guanidinium-catalyzed (168 .HBArF4) phospha-Mannich reaction of

di-1-naphthyl phosphine oxide 125 and various imines

x mol% 168 .HBArF4THF, -50 or - 60oC

R1

R2O

NTs

R P

R1

R2O

a Isolated yield b Determined by chiral HPLC analysis c the absolute configuration of

169c was assigned using X-ray crystallographic analysis d tBuOMe as solvent e

DCM:Et2O 1:1 as solvent f PG (imine) = 4-phenylbenzenesulfonyl g PG (imine) = benezenesulfonyl

3.2.3 Phospha-Mannich reaction of H-phosphinates

3.2.3.1 Optimization study of phospha-Mannich reaction of H-phosphinates and

imines

The H-phosphinate such as benzyl benzylphosphinate 179a was another type of

phosphorus nucleophile The H-phosphinates were prepared from the literature

reported protocol (Scheme 3.6) Following the reported reagents and conditions9, a

mixture of H-phosphinic acids 177 and phosphinic acid 178 were obtained The

phosphinic acid 178 were undesired product and generated from the double attack of

the intermediate 176 The modified protocol employed 0.5 eq of corresponding

benzyl bromides rather than 1 eq of alkylation reagents The slow dropwise addition

of benzyl bromide was the key to increase the selectivities and to improve the yields

of H-phosphinic acid 177 The reaction mixture was conducted the next step without

further purification after a simple acid-base work-up H-phosphinate 179a were

finally obtained with high yields via Hewitt reaction.10

OH Bn O H TMSO P OTMS

iii

P

OBn Bn O H

179a 175

Scheme 3.6 Synthesis of benzyl benzylphosphinate Reagents and conditions: (i)

1.05 eq (TMS)2NH, 110 oC, 1-2h; (ii) 0.5 eq benzylbromide, DCM, 0 oC to rt (iii) benzyl chloroformate, pyridine, DCM, rt to reflux, 15 min

It was found that the addition of rac-benzyl benzylphosphinate 179a to imines can

be catalyzed by 168 .HBF4 (Scheme 3.7) However, the reaction was slow at room

temperature and low ee was observed (<5% ee) The products 180a contained two

chiral centers and the definition of relative configuration was shown in the Figure 3.2

5 mol% 168 .HBF4toluene, r.t.

syn-180a

+

Ph NHTs P

OBn Bn O P

Bn OBn O

+

24 h, < 20% conv < 5% ee

Scheme 3.7 Guandinium 168 .HBF4 catalyzed phospha-Mannich reaction of

rac-benzyl benzylphosphinate 179a to imine

Ph

NHTs

P BnOBn O

HC

HC

HP

HP

Group of highest priority on carbon center (HC) and group of highest priority on phosphorus

center (HP) are the opposite side - anti configuration

Group of highest priority on carbon center (HC) and group of highest priority on phosphorus

center (HP) are the same side - sy n configuration

Ph

NHTs

P BnOBn O

HC

HP

Figure 3.2 The definition of the relative configuration of 180a

Table 3.4 Guanidinium-catalyzed phospha-Mannich reaction of benzyl

benzylphosphinate 179a

179a

5 mol% catalyst toluene, temp

10 eq K2CO3

syn-180a

+

Ph NHTs P

OBn Bn O P

Bn OBn O

K2CO3 was used as an additive and significant acceleration of reaction rate was

observed without decreasing the ee (Table 3.4, entry 1) Guanidinium salts with

different counterions were investigated (entries 2-5) Catalyst 168 .HPF6 gave similar

results in terms of reaction rate and ee (entry 2) When the catalysts with the

counterions Cl- and ClO4- were employed, the reaction can reach 100% conversion

less than one hour; but the ees decreased dramatically (entries 3 and 4) Catalyst

168 .HBArF4 gave the most promising result under the same condition (entry 5) Better

result was observed when reaction temperature was lowered to –20 oC although long

reaction time was required (entry 6) After the reaction completed, the catalyst was

recovered and NMR characterization revealed that the guanidinium catalyst

168 .HBArF4 was unchanged; the catalyst was not converted to guanidine 168 during

the course of the reaction

Different solvent systems were also tested in the phospha-Mannich reaction

When DCM was used as the solvent, better ee was observed but the reaction rate was

much slower (Table 3.5, entry 2) Racemic 179a was used as limiting reagent (Table

3.4, entries 1-6 and Table 3.5 entries 1 and 2) in these experiments, resulting in a

diastereomeric ratio (dr) of 1:1 When the amount of imine increased to 1:2 (entry 3),

the ee of both diastereoisomers improved Furthermore, more promising results were

demonstrated when the amount of racemic donor 179a was increased to 2:1 (entry 4);

the ee of the major diastereoisomer (syn) was increased to 82% In addition, the other

chlorinated solvent CHCl3 was tested, but only about 40% conversion was observed

even after 4 days (entry 5) A compromised solvent mixture (DCM: toluene, 1:1) was

used to make a balance between reaction rate and ee (entry 6) When the amount of

179a was increased to 2:1 (entry 7), the ee of major diastereosiomer was improved to

89% and dr was also improved to 4:1

benzylphosphinate 179a.

179a

5 mol% 168 .HBArF4

-20oC 10eq K 2 CO 3

syn-180a

+

Ph NHTs P

OBn Bn O P

Bn OBn O

a Determined by TLC, 100% conversion b Determined by HPLC c Approximated by

1H NMR and confirmed by HPLC d 40% conversion (estimated by TLC)

Scheme 3.8 Synthesis of phosphinates bearing different phosphinic acid easters

Reagents and conditions: (i) triphosgen, DCM, sealed tube; (ii) DCM, 1eq pyridine,

rt to reflux

Table 3.6 The addition of benzyl phosphinates with different protecting groups to

imines

5 mol% 168 .HBArF4toluene, -20oC 10eq K2CO3

sy n-183

+ P

Bn OR O

Ph NHTs P

OR Bn O

a Donor : acceptor = 2:1 b Determined by TLC, 100% conversion c Determined by

HPLC d Approximated by 1H NMR and confirmed by HPLC

A series of benzyl phosphinates bearing different protecting groups were

synthesized from the corresponding benzyl alcohols 181 (Scheme 3.8) The protecting

groups of benzyl phosphinates can perform as auxiliary groups to provide the

potentially steric and electronic effect to increase optical purity These phosphinates

were employed in the phospha-Mannich reaction (Table 3.6) The enantioselectivities

of major diasteroisomers of phosphinates with electron-donating and

electro-withdrawing substituents (182a and 182b respectively) decreased dramatically

(entries 1 and 2) The phosphinate with more sterically hindered 2-naphthyl group

was expected to increase the ee; however, the ee dropped to 65% for major

diastereoisomer

The effect of different protecting groups on imines was investigated in the

phospha-Mannich reactions (Table 3.7) The N-benzenesulfonyl and

N-p-nitrobezenesulfonyl imine both gave the similar level of enantioselectivity

(entries 1 and 2) The imine with more steric hindrance mesitylenesulfonyl group

could not afford decent conversion after 48 hours (entry 3) Other types of protecting

groups were also tested in the phospha-Mannich reactions However, the reactions of

the tert-butyl carbonate (Boc) and benzyl protected imines were slow and the results

in terms of enantioselectivieties and dr were not determined (entries 4 and 5)

Table 3.7 The phospha-Mannich reaction of imines with different N-protecting

groups

5 mol% 168 .HBArF4toluene : DCM 1:1, -20oC 10eq K2CO3

syn-184

+ P

Bn OBn O

179a

Ph NHPG P

OBn Bn O

a Donor : acceptor = 3:1 b Determined by TLC, 100% conversion c Determined by

HPLC d Approximated by 1H NMR and confirmed by HPLC