Phosphonium salt in asymmetric catalysis

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Title: Phosphonium salt in asymmetric catalysis: a journey of a decade’s extensive research work Authors: Ajij Golandaj, Akil Ahmad, and Deresh Ramjugernath This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700795 Link to VoR: http://dx.doi.org/10.1002/adsc.201700795

10.1002/adsc.201700795

Advanced Synthesis & Catalysis

REVIEW DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Phosphonium salts in asymmetric catalysis: a journey of a decade’s extensive research work Ajij Golandaj*, Akil Ahmad and Deresh Ramjugernath Thermodynamics Research Unit, School of Chemical Engineering, University of KwaZulu-Natal, Howard College Campus, Private Bag X54001, Durban, 4041, Republic of South Africa.; email:[email protected] Received: (will be filled in by the editorial staff) Abstract: The first report on a phosphonium salt as an asymmetric catalyst was published in 1997, and thereafter this area of research remained fairly dormant for almost a decade. However, the second decade (2007-2017) has recorded a significant growth in the published literature and emerged as a hot topic of research. The use of phosphonium salt as a phase transfer catalyst has gained momentum in recent years due to their ease of availability and simple preparation technique. Most of these asymmetric phosphonium salts are derived from readily available starting materials like chiral amino acids and binaphthyl rings. With a simple modification in the basic core of these moieties, they can be used to execute a number of enantioselective organic transformations.

1. Introduction Biological response is only generated when the molecule with a specific spatial arrangement fulfills the receptor’s stereo chemical requirement[1]. Nature utilizes its own tools to obtain these molecules in the required spatial arrangement, for instance, enzymes like hydrolases and lipases are versatile and selective chirality inducing agents[2]. Chemists should be thankful to nature for providing access to the naturally occurring chiral compounds such as amino acids and sugars, with the help of which a conceptual understanding of asymmetric synthesis is being developed[3]. Usually, chiral induction in an achiral molecule is achieved with the aid of chiral template (an organic molecule) linked to a transition metal or a heteroatom. During the course of the reaction, the achiral molecule forms a systematic and reactive transition state with the chiral template through hydrogen bonds and/or static interactions. Subsequently, the incoming nucleophile approaches the electrophilic carbon through the less-hindered side of the transition state to yield a chiral molecule.

This review comprises a comprehensive overview of the historical development of catalyst design, with its necessary modification and applications in selective organic transformations. 1. 2. 3. 4. 5. 6.

Introduction Previous work P-spiro tetra amino phosphonium salts 1,1’-Binaphthyl based phosphonium salt Amino acid based phosphonium salts Conclusion

Keywords: asymmetric catalysis, phosphonium salts, chiral tetraaminophosphonium, 1,1’-binaphthyl, amino acid

Transition metal asymmetric catalysts are composed of expensive metals and ligands, which makes this choice uneconomical. Instead, heteroatom based chiral organocatalysts provide a better alternative, as they are readily available or can be easily synthesized in the laboratory[4]. In general, organocatalysis could be categories in five different subclasses (i) secondary amine catalysis via enamine, (ii) secondary amine catalysis via iminium ions, (iii) phase transfer catalysis, (iv) nucleophilic catalysis and BrØnsted base catalysis; and (iv) H-bonding catalysis[5]. These subclasses have their own synthetic importance and are commonly used to achieve various asymmetric organic transformations utilizing a single organic solvent or two miscible solvents, except phase transfer catalysis (PTC). PTC provides an option to use two immiscible phases together in a reaction, i.e. liquidliquid or solid-liquid[6], where the monophasic reaction fails to proceed, due to the limited solubility of reagents in the given organic solvent. Catalysts used in this type of reactions are ionic in nature, in which the heteroatom (linked to a chiral organic molecule) carries the positive charge, while stabilizing the charge with a negatively charged counter ion[7]. The ionic

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Advanced Synthesis & Catalysis

nature of phase transfer catalysts makes them a suitable candidate to use in conjunction with water (as a polar phase), as it facilitates the ion or molecule transfer from organic to aqueous phase, by virtue of it accelerating the rate of heterogeneous reaction[4a]. The phase transfer catalysts are also useful in various aspects, like controlling the solubility of the reagents in substrate phase, product separation, operation under milder reaction conditions, being environmentally benign, and most importantly, they are tolerant to air, moisture and water, which makes them a promising and an efficient candidate for green chemistry applications[4a, 8]. The phase transfer catalysts that are used in asymmetric transformation are mostly quaternary onium salts, mainly nitrogen (N) and phosphorous (P) based chiral units, existing with a counter anion, generally halides[6, 8a, 9]. The N-based phase transfer catalysts have already proven themselves as ideal candidates for asymmetric transformations[6]. Likewise, research in the last decade over P-based phase transfer catalysts ascertained that to some extent the P-based phase transfer catalysts are also as good as the N-based phase transfer catalysts for chirality induction. This review is dedicated to unfolding the emergence of asymmetric phosphonium salts and their development to date with the inclusion of catalyst design. Catalyst design is an important aspect of asymmetric catalysis, which is often ignored, as most reviews focus on the catalyst’s applications. Few introductory reviews that have been previously published are focused on the applications of phosphonium salts[9b, 9c, 10]. However, this review is themed on an in-depth and comprehensive discussion of catalyst design and transition states involved during reaction with a brief summary of the reaction condition, product yield, enantioselectivity, and its scope for organic transformation.

Dr Ajij Golandaj is currently pursuing post-doctoral research in the Thermodynamics Research Unit with Prof. Deresh Ramjugernath in the School of Chemical Engineering, University of KwaZulu-Natal, Durban, South Africa. He studied B.Sc. in chemistry at Shivaji University, Kolhapur (Maharashtra, India) and then finished his M.Sc. study in Organic Chemistry at University of Pune, Pune (Maharashtra, India). After working in the pharmaceutical industry for 3 years, he moved to Durban, South Africa to undertake his PhD study with Professor H. B. Friedrich and Dr. S. Singh in the Catalysis Research Group, School of Chemistry, University of KwaZulu-Natal. His research interest includes synthetic organic chemistry and heterogeneous catalysis. Professor Deresh Ramjugernath is the Deputy Vice-Chancellor: Research, at the University of KwaZulu-Natal. He is also the DST/NRF South African Research Chair for Fluorine Process Engineering and Separation Technology, and the Co-Director of the Thermodynamics Research Unit. Prof. Ramjugernath leads a large team of postgraduate students and researchers - arguably one of the leading research groups in the field globally - which undertakes cutting-edge research contributing towards chemical process development and optimization in South Africa and abroad. His research interests involves chemical thermodynamics, organic chemistry and catalysis. He has authored over 290 peer-reviewed scientific publications. Prof. Ramjugernath is actively involved in a number of initiatives in innovation, commercialization and entrepreneurship in South Africa.

2. Previous Work (1997-2007) Before the use of phosphonium salts as an asymmetric catalyst, it was treated as an ylide reagent, mainly for carbonyl olefination reactions. Besides that, it was also used as a pesticide[11], while some efforts were also dedicated for its use as a stoichiometric reagent and as ionic liquids[12]. In 1997, Shioiri et al. communicated the first report on phosphonium salt (binaphthylphosphonium hydrogen difluoride) 1 as an asymmetric catalyst for the asymmetric aldol reaction of benzaldehyde 2 and 2-methyltetralone enol silyl ether 3[13]. In the search for an efficient catalyst, they prepared several catalysts carrying different R1 and R2 groups (R1 = R2 = H, Me, n-Bu and Bn). However, the best results were obtained with catalyst 1a possessing benzyl (Bn) group at both R1 and R2 positions, which

Dr Akil Ahmad is working as a Postdoctoral Fellow in the School of Chemical Engineering, University of KwaZulu-Natal. He earned his PhD (Chemistry) from Aligarh Muslim University (AMU), India. Dr. Ahmad has more than 10 years of teaching and research experience. His research interests are in the areas of environmental pollutants and their safe removal, synthesis of nanoparticles and Nanosorbents, photocatalytic degradation, thermodynamic and kinetic studies. He has published more than 35 research, reviews articles and book chapters in journals of international repute and publishers.

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10.1002/adsc.201700795

Advanced Synthesis & Catalysis

OR1

1a R1 = R2 = Bn

PPh2 R2 HF 2

1 OTMS

O H

+

O

Catalyst 1a (10 mol%)

Me

OH Ph

o

THF, -70 C 6h

2

4

3

Yield 25%, ee 8.8%

Scheme 1 Silyl-mediated aldol reaction catalyzed by chiral quaternary phosphonium Salt 1

gave a 25% product yield with a highest enantiomeric excess (ee) of 8.8% in THF at −70 °C. Solvent change from THF to DMF, Et 2 O and to a mixed solvent system, such as THF-MeCN did increase the yield up to 94%, but at the expense of ee (less than 4.3% ee in all cases). Later in 1998, Manabe[14] successfully synthesized 1bromo-3,5-bis(bromomethyl)benzene derived phosphonium salts 5 using a hydrogen bonding strategy. In asymmetric catalysis, hydrogen bonding plays a major role in geometry fixation of ion-pairs and sequentially decides the enantiomeric excess of the product[15]. They created a multiple hydrogenbonding site by introducing two –NH and two –OH groups in the catalyst structure with the aim of keeping the chloride ion in an asymmetric environment. Catalysts 5 with varying R-groups (R1 = R2 = Ph, (CH 2 ) 7 CH 3 , (t-Bu) 2 C 6 H 3 ) were prepared and employed in the benzylation reaction of tert-butyl-2oxocyclopentanecarboxylate 6 as shown in Scheme 2. R2

OH

O

NH

HO

R1

HN

O

Br

5a, R1= R2 = Ph PPh3

5 O

O

O

Catalyst 5a OtBu

6

O

PhCh2Br sat. aq. K2CO3, toluene 0 oC, 168 h

OtBu Ph

7 Yield 44%, ee 50%

Scheme 2 Asymmetric benzylation of oxopentanecarboxylate 6 using phosphonium salt 5

2-

Among these catalysts, the catalyst 5a bearing R1 and R2 as phenyl rings displayed the best ee (50%) with 44% yield at 0 °C in 168 h. Increase in temperature from 0 to 20 °C increased the product yield to 80%, but dropped the ee (38%).

Only these two pioneering studies in the field of phosphonium salt asymmetric catalysis were reported in the first decade (from 1997 to 2007). Even though the catalysts designed by Shioiri et al. and Manabe did not meet the expectations as an asymmetric catalyst, it opened a gateway to the new class PTC. The second decade (from 2007 to 2017) witnessed a significant growth in the published literature on the catalyst design and its applications in asymmetric transformations. Four leading research groups, namely Ooi et al., Maruoka et al., Ma et al., and G. Zhao and co-workers, are the main contributors in the development of field. The novel chiral phosphonium salts designed by these groups are obtained from amino acids and the 1,1’-binaphthyl backbone. Depending on the catalyst’s basic structural design, these catalysts are divided into following subclasses; (A) P-spiro tetra aminophosphonium salts (B) 1,1’-binaphthyl modified phosphonium salts (C) Amino acid modified phosphonium salts All these groups are working in different research directions while applying a common idea of phosphonium salt asymmetric catalysis. Ooi et al.’s research work is focused on the P-spiro tetraaminophosphonium backbone, whereas Maruoka and co-workers exploring the 1,1’-binaphthyl backbone and G. Zhao et al. are developing amino acid modified phosphonium salts.

3. P-spiro tetraaminophosphonium backbone based phosphonium salts In 2007, Ooi et al. synthesized a novel chiral P-[5.5] spiro tetraaminophosphonium chloride 10 catalyst by reacting chiral 1,2-diamine 9 with phosphorous pentachloride (PCl 5 )[16]. However, the precursor chiral diamine 9 was sourced from (S)-valine 8 over four subsequent steps, using the method suggested by Wei et al. (Scheme 3)[17]. Although this chiral template has been sourced from an amino acid, i.e. (S)-valine, but owing to its versatile applications in asymmetric catalysis, this is discussed separately in this section. Typically, the molecular structure of catalyst 10 encloses two diazaphosphacycles linked almost perpendicular to each other through a cationic phosphonium ion, while the chloride ion is held in the structure with the aid of hydrogen bonds, provided by two –NH groups. During the course of the reaction, these –NH groups interact with the substrate through hydrogen bonds and perform a vital role in deciding the stereo chemical outcome. Moreover, the P−N bond of the tetraaminophosphonium backbone exhibits a high stability under a greater halide concentration, whereas under basic conditions the aminophosphonium ion generates a nucleophilic iminophosphorane. Ooi et al. designed several novel

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10.1002/adsc.201700795

Advanced Synthesis & Catalysis

catalysts using the P-spiro tetraaminophosphonium backbone by either manipulating the catalyst structure or by changing the counter ion and utilized it successfully in variety of asymmetric transformations. R

H ClH3N

1a. RC6H5MgBr, THF, rt, 24 h

COOMe

H 1b. HCl CbzN 1c. NH4OH H 2. CbzCl, Py o CHCl3, 0 C, 1h

8

OH

Table 1 Effect of nitroalkanes (1 to 3) and substrate scope (4 to 7) of (M,S)-10d catalyst for Henry reaction O

R

R

4. H2(50Psi), EtOH, 10% Pd/C, rt, 24 h

NH2

H CbzN

N3

R

R

Ar

PCl5, Et3N Toluene, 110 oC

Ar

H N

Cl

H N

H

P N H

N H H

(M,S)-10

tetraaminophosphonium

In the catalyst optimization study, catalysts with varying aromatic substituents (10a to d) were synthesized and used in asymmetric Henry reaction between benzaldehyde 2 and nitromethane 11 (Scheme 4) in the presence of a strong base such as potassium tert-butoxide (KOt-Bu).

Ar

R1

The catalyst 10d was found to be efficient in forming C−C bond between 13 and 14 with good to excellent yields, outstanding ee and high diastereoselectivities. Among the nitroalkanes, nitromethane gave the optimum result (entry 1 to 3). The substituents on the phenyl ring of 13 greatly affected the reaction time and yield to a lesser extent. The electronegative groups on the phenyl ring favoured high yield of the product in a shorter reaction time than the electron donating groups. Decrease in catalyst loading from 5 to 1% resulted in the prolonged reaction time. In their suggested transition state, the catalyst played a dual role i.e. base and a hydrogen bond donor (Figure 1). The catalyst 10 R1

H

Ph

+ MeNO 2

2

H Cl H N N P N N H H H

(M,S)-10

KOt-Bu THF, -78 oC, 8 h

Ar Ar

OH H

Ph

N

NO2

10a Ar = Ph, Yield 86%, ee 89% 10b Ar = m-Xylyl, Yield 36%, ee 45% 10c Ar = p-Tolyl, Yield 84%, ee 88% 10d Ar = p-CF3C6H4, Yield 90%, ee 94%

Scheme 4 Asymmetric addition of nitromethane 11 to benzaldehyde 2 in presence of catalyst 10

N H

H

KOt-Bu

(M,S)-10 H

O N

14

12

11

Ar Ar

OH

(M,S)-10 (5 mol%)

O

NO2

15

14 1

R1

Ar1

5 mol%/KOt-Bu THF, -78 oC, 8 h

R1

Ar Ar

Scheme 3 Synthetic scheme for chiral 1,2-diamine 9 and [5,5]-spirocyclic core (M,S)-10

3.1 P-spiro chloride salt

OH

Time aYield ee in % (d.r., (h) (%) anti:syn) 1 Ph H 8 90 94 2 Ph Me 8 93 97(>19:1) 3 Ph Et 8 78 96 (13:1) 4 2-FC 6 H 4 Et 5 94 96 (>19:1) 5 4-CH 3 C 6 H 4 Et 24 90 97(>19:1) 6 1-Naphtyl Et 8 84 96(>19:1) 7 2-Furyl Et 6 96 97(>19:1) a In both reactions, diastereomeric ratio (d.r.) was determined by 1H NMR analysis of crude

entry

H

9

H

13

R

(M,S)-10d

NO2

+

Ar1

3. NaN3, TFA, CHCl3, 0 oC, 1 h, rt, 4 h

H H 2N

Catalyst 10a with an unsubstituted aryl ring was found to give a better result than the catalysts with electron donating meta-xylyl 10b and para-tolyl 10c groups. In contrast, the catalyst 10d possessing paratrifluoromethylphenyl ring displayed an excellent yield and ee to the product 12. The catalyst 10d was then employed in reactions between different aldehydes 13 and nitroalkanes 14[16] (Table 1).

N N

N

R1

I

II

OH Ar2

H N

H O N O

H

N P N H

P

* R1 * NO2

O Ar2

H

13

Figure 1 Working hypothesis for phosphonium salt 10 for direct Henry reaction

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Advanced Synthesis & Catalysis

in the presence of KOt-Bu forms triaminoiminophosphorane (I), which further abstracts a proton from nitroalkane 14 to yield a nitronate anion. The nitronate anion, which is a bidentate hydrogen bond acceptor forms an ion pair (II) with the catalyst 10 to allow stereo selective addition of nitronate anion to 13. In 2013, Ooi and co-workers compared the activity of (S)-valine derived tetraaminophosphonium chloride 16 and triaminoiminophosphorane 17 obtained from (S)-isoleucine for Michael addition of azlactone 18 to the electron deficient alkynes 19 (Scheme 5)[18]. The results obtained over these two catalysts revealed that the precursor amino acid backbone has a great impact on the stereochemistry of newly formed alkene, since the catalyst 16 with M- and catalyst 17 with P-spiro chirality displayed the formation of Z- and E-alkenes, respectively[18]. Both the catalysts displayed excellent yields and good to excellent enantioselectivities. The catalyst 16, formed Z-alkene with E/Z-ratio of 1:>20, in the contrary catalyst 17 gave E-alkene with E/Z ratio of >17:1. It was claimed that the formation of Z-alkene results due to the ability of catalyst 16 to donate a proton through the less hindered side of α, β-π plane of allenic enolate (I) via C-protonation pathway (Figure 2), whereas with the catalyst 17, the formation of E-alkene was dominant and claimed to appear through O-protonation pathway to yield an intermediate (II) followed by 1-3 proton shift. H Cl N

H N

Ar Ar

P Ar Ar

N H

Me Me

N H

Me Me

N

Et Ph Ph

N Ph Ph

N

o

18 R1 = Bn, p-ClC6H4CH2, p-MeOC6H4CH2

H

(E)-isomer

H

I

(P,S )- 17 1,3-proton shift

O-protonation

RS

OR •

RL

O H II

Figure 2 Possible protonation pathway of enolate and allenic enolate

To observe C-protonation, the spatial environment around the acidic –NH protons of the catalyst should be free enough for proton transfer from the catalyst to the allenic enolate, like in case of catalyst 16. However, in case of catalyst 17, congested environment around N−H protons does not allow C-protonation pathway to occur and ultimately O-protonation is favored. To validate the O-protonation hypothesis, they further employed the Michael acceptor substrate with no oxygen, such as cynoacetylene 21 in the presence of catalyst 17 (Scheme 6). The various azlactones 22 were added smoothly to cynoacetylene 23 in the presence of catalyst 17 to form Z-alkenes 22, via αcyno-vinylic anion in good yields, excellent ee and high E/Z ratio. CN

23

O

17, 5 mol% O

O o

toluene, -78 C

19

22 O

MeO O R1 N

Ph

(Z)-20

Yield 89 to 95% ee 85 to 90% E/Z ratio 1:>20

O

o

toluene, -60 C Ar1 = PMP

O

O

17, (5 mol%) MeO

O

CO2R

RL

O

R1

O

O

O Ar1

RL

CN R1 N PMP

PMP

toluene, -60 C Ar1 = Ph

N

RS

OR

N

16.HCl/KOtBu (5 mol%)

R1

(Z)-isomer

on



O

Ar = p CF3C6H4

O

RS

17

16.HCl

CO2R RL

tonati

C-pro

H

Et

P N H

RS

-16 (M,S)

R1 = Bn, p-ClC6H4CH2, p-MeOC6H4CH2, o-FC H CH 2, 6 4 3,5-(MeO)2C6H3CH2, Et, Me(CH2)3, Me(CH2)5, MeS(CH2)2, Me2CHCH2, Me2CH, Ph

(Z)-24 Yield 72 to 88%, ee 90 to 97%, E/Z ratio 1:>20

Scheme 6 Substrate generality of chiral iminophosphorane 17 catalysed Z-enantioselective Michael addition of azlactones 22 to cynoacetylene 23

R1 N PMP (E)-21 Yield 92 to 98%, ee 90 to 93% E/Z ratio >17:1

Scheme 5 Catalysts structure and its reaction scope for Eand Z-selective asymmetric Michael addition of azlactones 18 to the methyl propiolate 19

In this reaction as well, the protonation of allenic anion (25 and 26) is dependent on the steric demand of alkene and it would occur through the opposite side of the bulky group 26 to give Z-alkene, since no oxygen is present for O-protonation (Figure 3). The contrary behavior of catalyst 17 with two different substrates could be accounted for the presence and absence of the

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Advanced Synthesis & Catalysis

oxygen in substrates, which in turn decides the stereochemistry of the newly formed alkene. H RS

RS

CN

RL

25

RL

H

+

CN

26

+

RS

RS RL

CN RL

CN

Z-isomer

E-isomer

Figure 3 Protonation pathways for α-cyano vinylic anion

3.2 P-spiro tetraaminophosphonium salt with different anionic counter ions In 2008, Ooi and co-workers tailored the catalyst 10a by replacing its counter ion and the resultant catalysts were exploited for direct Mannich type reactions between azlactone 27 and N-sulfonyl imine 28[19]. They proposed that, in addition to the structural modification, the efficiency of catalyst could also be improved by introducing tunable or functionalized organic anions. For this purpose, they used different organic carboxylate anions to balance or neutralize the charge on phosphonium ion, (Scheme 7). The replacement of the chloride ion was achieved OCOR-RCO2H Me N

H

N H

Ph

N H

H

N P

N H

Ph Ph

N H

(P,S)-29 OCOR

(M,S)-29 OCOR N

SO2Tol H

Ph O

N

Ph

Ph

Me

Me

H Ph

Ph H

P Ph

TolO2S

28

NH

O

catalyst 29

Ph N

27

Ph

O Ph

In 2009, Ooi and co-workers designed another catalyst using the tetraaminophosphonium backbone with phenol as a counter ion. In the catalyst, positive charge on the phosphonium ion was neutralized over three phenolic groups (instead halide) while forming a 10membered cyclic network, with the help of hydrogen bonds (Figure 4)[21].

OCOR-RCO2H

Me N

through an ion exchange method. They concluded that the basicity of anion plays a key role in determining the diastereoselectivity of product 30, as with increase in the basic strength of anions, the product diastereoselectivity was increased (from formate to pivalate). The highest enantioselectivity (60% ee) to syn isomer was observed with catalyst possessing Pspiro chirality, since this conformational isomer carries two of its N-H hydrogens on the same side, which interact with 27 through hydrogen bonds, thus providing the highest ee. Substrate scope study for the catalyst (P,S)-29-OPiv.PivOH was carried out by keeping the substituents of 31 and 32 at R1 and R2 the same (constant) while changing the substituents on the aromatic rings of both the substrates (Table 2). The ee and diastereoselectivity ratio (d.r.) of the product increased with the increase in the electron density on both the aryl rings, Ar1 and Ar2 (entry 1 to 5). In fact, the electron donating groups on aryl rings contribute to form a more tighter ionic pair of enolate oxygen with cationic phosphonium, via Coulombic force[20]. Further increase in ee up to 99% was achieved by dropping the reaction temperature down to –50 °C (entry 7 to 11).

THF -40 oC, time

O

Figure 4 Oak Ridge thermal ellipsoid plot diagram of 41·(OPh) 3 H 2 . (Hydrogens are omitted for clarity) (Reprinted from Ref. 18 with permission of The American Association for the Advancement of Science)

N Ph

Ph

>96% 30 (M,S)-29-OCHO: syn/anti = 1.3:1 6% ee (Syn isomer), 3.5 h : 1.2:1, 5% ee, 2 h 29-OAc M,S ( )(M,S)-29-OPiv : 1.3:1, 6% ee, 0.5 h (P,S)-29-OPiv : 1.6:1, 60% ee, 1 h

Scheme 7 Effect of catalyst 29 stereochemistry and counter ion on asymmetric addition of azlactones 27 to sulphonyl imine 28

The catalyst 34 was obtained over a series of steps, consisting anion replacement from chloride to hydroxide ion, followed by the treatment with phenol. The catalyst was then used for asymmetric addition of azlactone 35 to phenyl α,β-unsaturated acylbenzotriazole 36 (Scheme 8)[22]. Prior to arrival at the final structure of catalyst 34, they verified the effect of unsubstituted and substituted phenols (including electron donating and withdrawing

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Table 2 Effect of protective group (Ar1, Ar2) (entry 1 to 3) on stereoselectivity and substrate scope (4 to 16) of the direct Mannich type reaction of azlactones and N-sulphonyl imine the direct Mannich type reaction of azlactone O

R1

N O

N

+

(P,S) 29-OPiv. PiVOH 2 mol%

SO2Ar2

R2

Ar2O2S

THF -40 oC, time

H

Ar1

NH

O

R2

O

R1 N

Ar1

31

32

1

2

33

1

2

b

Entry Ar Ar R R Yield (%) d.r. (syn/anti) ee% 1 4-CH 3 O-C 6 H 4 4-tolyl PhCH 2 Ph(CH 2 ) 2 97 2.2:1 64 2 2-CH 3 O-C 6 H 4 4-tolyl PhCH 2 Ph(CH 2 ) 2 89 2.2:1 65 3 3,4,5-(CH 3 O) 3 -C 6 H 2 4-tolyl PhCH 2 Ph(CH 2 ) 2 98 2.6:1 75 4 3,4,5-(CH 3 O) 3 -C 6 H 2 mesityl PhCH 2 Ph(CH 2 ) 2 99 2.9:1 93 5 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 Ph(CH 2 ) 2 95 6.7:1 95 6c 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 Ph(CH 2 ) 2 99 7.1:1 99 7c 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 CH 3 91 4.5:1 92 8c 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 CH 3 (CH 2 ) 7 92 6.6:1 96 9c 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 PhCO 2 CH 2 88 12:1 93 10c 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 (CH 3 ) 2 CHCH 2 94 4.4:1 95 11c 3,4,5-(CH 3 O) 3 -C 6 H 2 2,5-xylyl PhCH 2 Hex 98 2.3:1 90 a The reactions were performed at -40 ̊C using catalyst (P,S)-29-OPiv.PiOH (2 mol%). bDetermined by 1H NMR analysis. c Reaction conducted at -50 ̊C. O

O R1

Bt

Ph

Bt

36 O O

toulene -40 oC (Conc. 10 mM)

N

35 Me

Me

N

N P

Ph Ph

Ph

34 (1 mol%)

N H

O Ar H

N H

Ar O H

Ph Ph

38 O

N O

O

O

Toluene, -40 C

N

Me

Me

Me

Me

N

N

Et

Et Ph Ph

P

Ph Ph

N H

N H

Ar

HO

OH

Ar

O

34

Scheme 8 Effect of aryl substituents on yield and ee of the product 42 (Bt = benzotriazole)

groups) over the yield and ee of product 37. Among these, phenol with electron-withdrawing groups displayed a better ee, especially the 3-5dichlorophenol was excellent (yield 92% and ee 80%), which improved the ee to 89% (with 5 mol% catalyst). The enantiomeric excess was further increased to 95% (yield 95%), when the cationic phosphonium salt 34e prepared from (S)-isoleucine was utilized in the reaction. In the presence of catalyst 34e, addition of the azlactone 35 was achieved smoothly to several α,βunsaturated acylbenzotriazoles 38 (Scheme 9), irrespective to the nature (electron withdrawing or donating) of substituents. Reaction protocol also nicely accommodated fused ring, ring with heteroatoms, and primary and secondary alkyl groups.

O

O Bt N

39

35

O Ar

O o

37

34a Ar = Ph, Yield 99%, ee 60% 34b Ar = 4-MeC6H4, Yield 96%, ee 58% 34c Ar = 4-ClC6H4, Yield 97%, ee 75% 34d Ar = 3,5-Cl2C6H3, Yield 92, ee 80%

R1

31e (1 mol%)

O

Bt

R1 = p-MeO-C4H4, p-BrC6H4 o-MeC H m-Br-C H 6 4, 6 4 1-naphthyl, 2-Furyl, Me, Me(CH2)2, Ph(CH2)2, Cyclohexyl Yield 90 to 98%, ee 93 to 98%

Ar

34e Ar = 3,5 Cl2C6H3

Scheme 9 Substrate scope for asymmetric addition of azlactone 39 to various α,β-unsaturated acylbenzotriazole 43

Later in 2012, they employed the same catalyst 34e for conjugate addition of azlactone 35 to the nitroolefins 40. Prior to testing the catalyst, they examined the effect of 3,5-dichlorophenol addition on the δ value of triaminoiminophosphorane of catalyst 34 in THF at −98 °C using 31P-NMR spectroscopy[23]. Addition of 3,5-dichlorophenol to the solution containing triaminoiminophosphorane showed a significant influence on the δ value of phosphorous of 34 (Figure 5).

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Table 3 Substrate scope of substituted nitroolefins 40 for azlactone 35 addition in presence of catalyst 34e NO2

R1

40

O iPr

O N

R1

34e (2 mol%)

N

iPr

THF/DMF -60 oC

35

NO2 O

O

41 1

Figure 5 31P-NMR charts of aminophosphonium aryloxide 34 with addition of phenol in THF at -98 °C, ■: 34; ●: 34[ArOH]; ▼34[ArOH] 2. (Reproduced from Ref. 20 with permission from the Royal Society of Chemistry)

Doping triaminoiminophosphorane with 0.5 equivalents of 3,5-dichlorophenol, the 31P-NMR displayed a new peak at 37.7 ppm in addition to the peak at 44.4 ppm, with further increase in the 3,5dichloropheol equivalent to 1 and 1.25, the peak at 44.4 ppm disappeared and a new peak at 36.5 ppm started appearing besides the peak at 37.7 ppm. Increasing its equivalent to two and onwards, the only peak at 36.5 ppm remained visible. In fact, the addition of azlactone modifies the catalyst’s current state to form reactive enolate by replacing one of the phenol molecule in the catalyst 34. The presence of phenol in the catalyst structure appeared to be vital, since in the absence of it, the reaction favored the formation of oligomerised product (Figure 6).

Entry R Yield (%) d.r. ee (%) 1 p-MeO-C 6 H 4 93 >20:1 96 2 p-Br-C 6 H 4 91 >20:1 98 3 m-Br-C 6 H 4 99 >20:1 97 4 p-Me-C 6 H 4 89 >20:1 97 5 o-Me-C 6 H 4 90 >20:1 96 6 2-Naph 99 >20:1 96 7 2-Furyl 92 >20:1 91 8b N-Me-3-indolyl 86 >20:1 98 9 Cyclohexyl 82 4:1 94 a Reaction performed with 0.1mmol scale 40 with 1.1 equiv of azlactones 35 in THF/5% DMF (0.2 mL), b0.5 mL of THF/5%DMF was used due to the low solubility of N-Me3-indolyl.

3.3 P-spiro tetraaminophosphonium salt derived from chiral diamine In 2009, Ooi et al. designed and synthesized a new set of chiral phase transfer catalysts, utilizing the tetraaminophosphonium backbone. However, the tetraaminophosphonium backbone in this case was obtained from commercially available (R,R)-1,2diphenylethylenediamine 42 in two steps (Scheme 10)[24]. Ph

NH3Cl

Ph

NH3Cl

42

1. PCl5, Pyridine Et3N, DCM, rt 2. NaH, ArCH2Br CH3CN, DMF -40 oC, rt

Cl

Ar Ph

Ar Ph

N

N P

Ph

N

N

Ar

Ph Ar

43

43a, Ar = Ph 43b, Ar = 3,5-(Me3Si)2C6H3 43c, Ar = 3,5-(t-BuMe2Si)2C6H3

Figure 6 Oligomerised product formed in presence of iminophosphorane instead 34

Scheme 10 Synthetic route to tetraaminophosphonium backbone 43 using (R,R)-1,2-diphenylethylenediamine 42

The azlactone 35 added smoothly to different nitroolefins 40 under mild reaction conditions (Table 3). The reaction accommodated both electron withdrawing and donating substituents (entry 1 to 5) regardless of their position on the aryl ring and provided good yields and excellent ee. The heterocyclic and fused rings also showed no adverse effect on yield and ee (entry 6 and 7). The diastereomeric ratio was only lowered with the alkyl substituents (entry 9), albeit with good yield and excellent ee.

The tetraaminophosphonium chloride salt 43 was further explored for addition of amino acid (Boc-LAla-D,L-Phe) derived azlactone 44 to allyl halide under biphasic condition (aqueous K 3 PO 4 and organic solvent)[24]. The stearic requirement of catalyst 43 showed an enormous impact on the yield as well as on the d.r. of product, since the most sterically hindered catalyst 43c displayed an excellent result (Scheme 11). The solvent contribution in the reaction was observed to be minimal; in contrast,

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lowering the reaction temperature from 0 to −15 °C improved the yield to 86% (with d.r. 95:5). 43 (1mol%)

O O BocHN

O

Ph

Me

44

They further utilized the catalyst 43c for simple azlactone 48 addition to various allyl bromides (R-X) yielding product 49 with a quaternary carbon at αposition in excellent yields and ee, especially under solid/liquid (K 3 PO 4 /CPME) biphasic condition at – 30 °C (Scheme 12)[25]. The addition of azlactone to various bromo-functionalities was achieved with moderate to good yield and ee. However, the reactions with chloro(methoxy) methane (ClCH 2 OMe), methyl bromoacetate, (BrCH 2 CO 2 Me) and benzyl bromide (BnBr) precursors displayed a significant drop in the yield and ee.

O

Br N

considerable importance in peptide chemistry, since it provides an option of connecting different peptides together for peptide ligation.

solvent Sat. aq. K3PO4 0 oC

BocHN

N Me

Ph

45 , 43a Yield 26%, d.r. 64:36 43b, Yield 65%, d.r. 78:22 43c, Yield 78%, d.r. 94:6

Scheme 11 Effect of catalyst structure 43 on the yield and diastereoselectivity of the product 45

Further, Ooi and co-workers investigated applicability of the reaction protocol over various dipeptides-derived azlactones 46 for allylation with different alkyl bromides (Table 4).

O R1

Table 4 Asymmetric alkylation of dipeptide-derived azlactones 46 to alkyl halide using PTC 43c R-X

O R2

BocHN

N R1

AA1

AA2

46

CPME Sat. aq K3PO4, -15 oC

N

O Ph

O BocHN

O

R2 R1

R2X, K3PO4 TBME, -30 oC

O

43c (1 mol%)

O

43c (1 mol%)

O

N

Ph

R N

R2

R1

48 = (R Bn, CH2i-Pr)

49

1

AA1

47

Entry AA1 AA2

R-X Yield bd.r. 1 Leu Phe Br-CH 2 CH=CH 2 89 97:3 2 Val Phe Br-CH 2 CH=CH 2 94 99:1 3 Pro Phe Br-CH 2 CH=CH 2 74 93:7 4c Gly Phe Br-CH 2 CH=CH 2 77 91:9 5 Phe Phe Br-CH 2 CH=CH 2 82 97:3 6 Phe Trp Br-CH 2 CH=CH 2 93 91:9 7 Phe Leu Br-CH 2 CH=CH 2 97 97:3 8c Leu Leu Br-CH 2 CH=CH 2 98 95:5 9c Leu Leu BrCH 2 Ph 87 95:5 10e Phe Phe BrCH 2 C≡CH 97 98:2 11 Phe Phe BrCH 2 CN 88 91:7 12 Phe Phe BrCH 2 CO 2 Me 82 93:7 13e Phe Phe ClCH 2 OMe 66 95:5 a Reaction were carried out on a 0.1 mmol of 46 with 1.2 equivalents of alkyl halide, bThe diastereomeric ratio (d.r.) was determined by HPLC on a chiral stationary phase. d Reaction was performed at 0 °C. eAlkyl halide:5 eq.

They prepared several azlactones 46 from dipeptide, keeping one amino acid fixed and varying the other (entry 1 to 5), all combinations displayed excellent stereoselectivities. The trend was retained even after changing the amino acid of the azlactone moiety (AA2) from phenylalanine to tryptophan and leucine (entry 5 to 8). Moreover, the reaction procedure also accommodated the different alkyl halides including benzyl bromide, nitriles, alkenyl, ester and ether (entry 9 to 13), which displayed good yields and excellent stereoselectivities, excluding choro ether (entry 13). Product 47 of this reaction has

R2X= C3H5Br, BrCH2CMeCH2, a BrCH2CCH, BrCH2CO2Me, bClCH OCMe, bBrCH CH=CH 2 2 2, BrCH2C(me)=CH2, a BrCH2CCH, bBrBn

Yield 82 to 91%, ee 72 to 91% a

alkynyl compounds 63%, ee 74%

bYield

Scheme 12 Reaction scope of catalyst 43c for asymmetric alkylation of azlactones 48

4. 1,1’-Binaphthyl phosphonium salt

based

The 1,1'-binaphthyl ring is one of the most popular organic skeleton that has been exploited over the past few decades to execute chemical transformations, owing to its highly stable chiral configuration, paramount steric influence, and axial dissymmetric C2 symmetry (Figure 7)[26]. R' R R

R = functional groups R' = H or Ar

R'

50

Figure 7 Structural modification of 1,1’-binaphthyl unit at 2,2’ and 3,3’-position

In modern asymmetric catalysis, the chiral 1,1'binaphthyl motif has provided a new pathway to achieve the chemical transformations with high yields

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and enantioselectivities through its steric as well as electronic modifications, in particularly at R1 position (2 and 2’) for functionalization and R2 (3 and 3’) position for steric and electronic modifications[27]. Modification in the basic backbone of the 1,1'binaphthyl structure further enables its use in polar as well as non-polar solvents, especially in biphasic systems as a phase transfer catalyst, which is an important research area in green chemistry [27b, 28].

4.1 1,1’-binaphthyl phosphonium salt

membered β-keto ester rings took longer reaction times and gave lower yields or ee (entry 4 to 7). In their subsequent work, Maruoka et al. extended the application of catalyst (S)-55 for asymmetric Michael addition of 3-aryloxindoles 58 to methyl vinyl ketone (MVK), (Scheme 14)[31]. Table 5 Asymmetric amination of β-keto esters and βdiketone with chiral phase-transfer catalyst (S)-48 Ar

modified

Bu P Bu

Maruoka et al. used commercially available (S)binaphthol 51 as a starting material to functionalize the binaphthyl ring over a series of steps to achieve unsubstituted catalyst 52 (Scheme 13)[29].

a-c

Br

d

O CO2tBu

R P

Br

OH

Ar

CO2tBu

substrate

Base Condition Yield ee b (equiv) ( °C, h) (%) (%)

O

1

Ar Br

a, e

N CO2tBu

R

P

Br

R

OH

-20, 14 99

91

CO2tBu

K 2 HPO 4 (5)

-40, 70 97

90

CO2tBu

K 2 HPO 4 (1)

-20, 22 99

89

K 2 HPO 4 (5)

-40, 16 99

95

CO2tBu

K 2 HPO 4 (1)

-20, 40 99

92

COC6H9

K 2 HPO 4 (5)

-20, 84 75c

87

O

R

b-d

K 2 HPO 4 (1)

CO2tBu

Br

OH

NHCO2tBu

57

(S)-52 Br

O

Base, Toluene

56

Entry (S)-51

Ar = 3,5-(CF3)2-C6H4

Ar

(S)-55 (S) 55 t-BuO2CN=NCO2t-Bu

Br OH

Br

2

MeO

O

Br

(S)-53

Ar

Ar

(S)-54

Scheme 13 Synthesis of 2,2’-substituted, and 3,3’; 2,2’substitutued 1,1’ binaphthyl based catalysts a Tf 2 O, Et 3 N, CH 2 Cl 2 . bMeMgI, NiCl 2 (PPh 3 ) 2 , ether. c NBS, benzoyl peroxide, cyclohexane. dPHR 2 Toluene. e ArB(OH) 2 , Pd(OAc) 2 , PPh 3 , K 3 PO 4 , THF. (R = alkyl or aryl)

To obtain 3,3’-substituted catalyst 54, bromo derivative of (S)-binaphthol 53 was used and later it was subjected for coupling reaction with aryl boronic acid.

3 Cl O

O

5

tBuO2CN

O

6 O

O

K 2 HPO 4 -20, 84 99b 73 (5) F a Reaction was carried out with 1.2 equiv. of di-tert-butyl azodicarboxylate in presence of 3 mol% of (S)-55 and base in toluene.. b5 mol % of catalyst and 10 equiv. of azodicarboxylate were used. c5 equiv. of azodicarboxylate used.

7

Utilizing the synthetic method above, Maruoka et al. synthesized catalyst (S)-55 and employed it in asymmetric amination reaction of cyclic β-keto ester 56 (Table 5)[30]. In the reaction, the choice of base and its equivalents affected the ee of the product 57, for instance, the use of K 2 HPO 4 instead, K 2 CO 3 furnished the product with slightly higher ee and use of excess K 2 HPO 4 in reaction contributed significantly to obtain an excellent ee. The electronic nature of substituents present on the ring did not affect reaction yields and ee, since both electron withdrawing and donating groups displayed comparable results (entry 2 and 3). The reaction worked well with five membered β-keto ester rings in shorter reaction times but with aliphatic and six-

CO2tBu

4

Ph

OtBu

They revealed that the stearic effect exhibited by base and the reaction temperature affected yield and ee. Unlike in amination reactions (Table 5), K 2 HPO 4 was not effective for this transformation, even in excess amount. Instead, the bulkier potassium benzoate displayed an excellent ee compared to sodium and potassium acetates, especially at lower temperatures. The oxindole moiety 58 with electron donating and

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withdrawing groups showed no difference in reactivity and displayed almost similar yields and ee to the corresponding products. The catalyst (S)-55 was also employed in asymmetric Mannich addition of 58 to imines, but it displayed moderate to good ee (56 to 88%) with excellent yields. The reaction product 59 could be further utilized in the preparation of natural products such as CPC-1, (−)-physostigmine and (−)pseudophrynaminol etc.[32]. Y

Ph CHO

+

O

O

H2O, mesitylene 0 oC, 24 h

N Boc

N Boc

64

63

65 Bis-phosphonium salts

Ph

2Br O

PPh2

O

PPh2

Ph

P

2Br Ph

O

Y

CHO

Ph

62 (1 mol%)

Ph

Ph Ph

PPh2 Fe

2Br

P

Ph

PPh2

Me

Ph

X

O N Boc

catalyst (S) 55, CH2=CHCOR

R

X

Ph

Monophosphonium salts

O

PhCO2K (5 eq.) o toluene, -60 C, 24 h

PPh2

N Boc

58

Br

2Br

P Ph

PPh2

59

62c Yield 5%, ee 2%

62b Yield 13%, ee 8%

62a Yield 9%, ee 8%

*

Ph

Br

P Ph

Yield 91 to 99% ee 94 to 99%

X = H, 5-F, 7-F, 6-Cl, 6-CF3, 5-Me, 5-MeO Y= H, 4-F, 3-Cl, 4-Cl, 4-Ph 2-Naphthyl, 3-Me, 4-Me, 4-MeO

62d Yield 5%, ee 6%

Encouraged by the results obtained with catalyst (S)55 in asymmetric amination and Michael addition, they further undertook a task of synthesizing monoand bis-phosphonium salts by reacting the commercially available chiral phosphines 60 with benzyl bromide (Scheme 15).

60

Br

PhCH2Br toluene, 110 oC

*R P 3

Ph

61

commercially chiral quaternary available chiral phosphonium salt phosphine Scheme 15 Synthesis of chiral phosphonium salts

Ph

PPh2

Ph

PPh2

Br

PPh2

Br PPh2

Br OMe

62g Yield 97%, ee -25%

OH

62h Yield 96%, ee -26%

62i Yield 96%, ee 69%

Scheme 16 Asymmetric addition of 3-substituted oxindole 63 to acrolein 64 in presence of various 1,1’-bynaphthelene derived phosphonium catalyst (56a to i)

The proposed activation of enolate (Figure 8) in the presence of bifunctional catalyst (possessing phosphonium (P in +4) and hydroxide) 62i commences through hydrogen bonding with the substrate, although with Ar

* PPh2 Ph

Ph

Ar

* PPh2

O H O

Further, they employed the prepared phosphonium salts 62 in asymmetric addition of N-boc protected 3aryloxindole 63 to acrolein 64 (Scheme 16). Upon screening these bis-phosphonium (62a to d) and mono-phosphonium salts (62e to i), they revealed that the product yields obtained in the presence of 1,1’binaphathyl derived mono-phosphonium salt were better than the bis-phosphonium salt. In terms of enantioselectivity, the ee obtained with the use of mono-phosphonium salt was very poor, except catalyst 62i. This exception was attributed to the presence of –OH group, which was claimed to be involved in hydrogen bonding with reaction substrates[33].

62f Yield 18%, ee 1%

62e Yield 9%, ee 4%

Ph

Scheme 14 Asymmetric Michael addition reaction of 3phenyl oxindole 58 using phase transfer catalyst (S)-55

*R P 3

P

Ph

O N

O Boc

H O

N Boc

A

H

B

Figure 8 Proposed working model for bifunctional catalyst 62i

two possibilities were suggested (A) an enolate anion forming hydrogen bond with the hydroxyl group of 62i, (B) the –OH group interacting with the Michael acceptor and at the same time the cationic phosphonium center interacting with the enolate[33d-f, 34] . In addition to the catalyst (62i) backbone, the benzyl group on the phosphonium ion of and its substituents

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also affected the ee of product 65. Even the substituents nature and its position on the benzyl ring exhibited a significant impact on the outcome of reaction. The electron withdrawing groups (F, CF 3 ) situated at meta-position (3 and 5 position) favored high ee (>80%). The ee was even increased to 90% when 3,5-dinitro benzyl substituent (62j) was used. However, the ortho-substituents displayed a detrimental effect on the ee. The catalyst 62j was then used to expand the scope of the reaction by using 3aryloxindoles 66 (Scheme 17). The electronic nature of the groups present on the 3-aryloxindole moiety 66 showed no effect on the result of the reactions since the electron donating and withdrawing groups gave excellent yields and ee. Even with the vinyl ketone as well, the addition of 66 achieved smoothly in excellent yields and ee. The presence of water in reaction was determined to be must since in the absence of it the reaction was sluggish.

C Ph

Catalyst 56j (0.1mol%) O

PPh2 Br O R

(S)-62 or 68

Ar1 PPh2 H N

H

R' O

(S)-69

67 66 Br

70a R" = Ph, Yield 5%, ee 60% 70b R" = Me, Yield 6%, ee 48%

PPh2

Ar PPh2

69a Ar1 = Ph, R' = Ph, Yield 80%, ee 92% 69b Ar1 = 3,5-(CF3)2-C6H3, R' = Ph, Yield 80%, ee 94 69c Ar1 = 3,5-(t-Bu)2-C6H3, R' = Ph, Yield 98%, ee 94% 69d Ar1 = Ph, R' = Me, Yield 38%, ee 84% 69e Ar1 = Ph, R' = t-Bu, Yield 56%, ee 5%

Ph

Yield 94 to 96% ee 88 to 90%

R1 = H, F, MeO, Me

72 62i Ar = Ph, R = H, Yield 82%, ee 42% 68a Ar = Ph, R = Me, Yield 29%, ee 17% 68b Ar = 3,5-(t-Bu)2-C6H3, R = H, Yield 60%, ee 44% 68c Ar= 3,5-(t-Bu)2-C6H3, R = H, Yield 98%, ee 48%

Ar

Boc

CO2tBu SPh

71

56

N

O

Catalyst

H2O/Toluene (ratio 10:1), rt, 24 h

O

0 oC, 24 h

Boc

+

R1

H2O/mesitylene

N

O

O

64 H Ph

SPh N O

CO2t-Bu

O

Br

O

R1

reaction and a phosphonium center in the catalyst is a must to achieve excellent result, since the reaction

H N

-

Ar = 3,5 (NO2)2C6H3

S

O

Br OH

R'' O

(S)-70

62j

Scheme 17 Asymmetric addition of different oxindoles to acrolein in presence of catalyst 62j

Scheme 18 Effect of functionalized 1,1’-binaphthyl based catalyst ( 62i, 68 to 70) over asymmetric sulfenylation of β-keto ester SR

Further Maruoka and co-workers replaced the –OH group on catalyst 62i with ether 68a, amide 69 and sulphonamide 70 functionalities and the resultant catalysts were tested for asymmetric sulfenylation of tert-butyl 1-oxo-2-indanecarboxylate 56 (Scheme 18)[35]. Catalysts 62i, 68b and c displayed better yields with low ee, in contrast, catalyst 69 with amide functionality performed extremely well, especially with benzamide group (69a to 69c) displayed good to excellent yields with outstanding ee. Replacing the benzamide to aliphatic amides lowered the product yields and ee. In the presence of catalyst 69c, sulfenylation reaction proceeded smoothly with electron-withdrawing and electron-donating groups on aryl ring 73 and various N-substituted sulphides 74 were also accommodated (Scheme 19) with excellent yields and enantioselectivities. The presence of water in the

O

CO2t-Bu O

N

73 Y= H, F, Cl, OMe

CO2t-Bu SR

69c (0.1 mol%) H2O/toluene Y (ratio 10:1), rt, 48 h

+ Y

O O

74 R = 4-MeC6H4, 4-ClC6H4, 3-CF3C6H4, 2-MeC6H4, Bn

75 Yield 93-99%, ee 93-95%

Scheme 19 Asymmetric sulfenylation of 1-Oxo-2indanecarboxylates 73 using catalyst 69c

with phosphines; precursor of the phosphonium salt, showed only traces of product and in the absence of water, reaction was sluggish. Though the catalyst 69c was found excellent for the sulfenylation reaction, it displayed a poor ee (53%) for the chlorination reaction. Instead the catalyst with a slightly acidic group i.e. sulphonamide 70a was found to be excellent and raised the ee from 53% to 90% (Scheme 20).

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Cl

O CO2t-Bu O

N

+

Z

O O

Y

70a (1 mol%) H2O/toluene (ratio 10:1), Y rt, 24 h

CO2t-Bu Cl Z

77

76

78 Yield 99 and 90%, ee 92 and 94%

Y = F, Cl Z = C,O

Scheme 20 Asymmetric chlorination of β-ketoesters 76 using catalyst 70a

The catalysts 62i, 69a and 70a were also employed for asymmetric arylation of the 3-phenyloxindole 79 using 2-4-dinitrofluorobenzene 80 as an aryl source, but they realized that the choice of catalysts was not suitable (Scheme 21)[36]. Boc

Boc

NO2

O N

catalyst

Ar1 NO2

80

79 Ph Br PPh2 X

Ar Br PPh2 H N

H N O

81

O N

F

Ar'

Ar2

toluene, 25 oC

Ar1

82

(S) 62j = X = OH, Yield 98%, ee -12% = NHBz, Yield 89%, (S) 69a ee 35% = NHSO2Ph, (S) 70a Yield 36%, ee 3% Bz = benzoyl (S) 81a Ar = Ph, Ar' = Ph, Yield 46%, ee 64% 81b Ar = Ph, S ( ) Ar' = 3,5-(CF3)2-C6H3, Yield 42%, ee 79% = 81c Ar S Ph, ( ) Ar' = 3,5-(MeO)2-C6H3, Yield 49%, ee 76% (S) 81d Ar = 3,5-(CF3)2-C6H3, Ar' = 3,5-(CF3)2-C6H3, Yield 30%, ee 76% e = 81 Ar S 3,5-(tBu)2-C6H3, ( ) = Ar' 3,5-(CF3)2-C6H3, Yield 50%, ee 87% 81f Ar = 3,5-(tBu)2-C6H3, S ( ) Ar' = 3,5-(MeO)2-C6H3, Yield 85%, ee 84% e 81 Ar = 3,5-(tBu)2-C6H3, S ( ) Ar' = 3,5-(CF3)2-C6H3, c Yield 90%, ee 88% (S) 81e Ar = 3,5-(tBu)2-C6H3, Ar' = 3,5-(CF3)2-C6H3, Yield 99%, ee 91%b,c

Scheme 21 Catalyst structure optimization for asymmetric arylation of 3-phenyl oxindole 79 a Reaction conditions: 79 (0.050mmol), 80 and KHCO 3 (0.075mmol) catalyst (5 mol%), toluene (1.0 mL) at 25 °C. b Reaction performed at −20 °C with K 2 CO 3 (0.038 mmol) as a base. cIsopropyl ether was used as solvent

Thus, to improve enantioselectivity of product 82, they further modified the catalyst structure by introducing urea functionality on the binaphthyl ring at the place of hydroxyl and amide group of catalyst 62i and 69a respectively. The presence of urea functionality in the catalyst was claimed to improve the ee through hydrogen bonding with the substrate[37]. With the modified catalysts (S)-81a-e, the asymmetric arylation of 79 was achieved with better ee (>60%), under mild reaction condition using KHCO 3 as a base. Change in the solvent from toluene to isopropanol (i-Pr 2 O) improved the yield and ee to a lesser extent. The catalyst (S)-81e with bis-3,5(CF 3 ) 2 C 6 H 3 group on urea and phosphonium carrying 3,5-(t-Bu) 2 C 6 H 3 CH 2 group was found to be excellent in achieving arylation reaction with 99% yield and 91% ee in isopropanol at −20 °C. The arylation of substituted 3-aryl oxindoles 83a and 83b were achieved smoothly in high yields and excellent ee (83-94%) without any interference of the substituents present on indole 83a as well as on the aryl ring 83b, irrespective of their nature or type (Scheme 22). Moreover, the reaction protocol was also found to be suitable for the synthesis of 3heteroaryl and fused oxindole moieties with ee of 82%. Boc O

N

+

F

Ar

Boc

81e or f (5 mol%) base, iPr2O

NO2

N

NO2 Ar

NO2

NO2

80

83

O

84 Boc

Boc

N

O

N

O

X Ar

Ph

83a X = 5-H/Me/OMe/F, 4-Cl Yield 86 to 99% ee 83 to 94%

83b Ar = p-CH3C6H4, p-CF3C6H4 p-FC6H4, p-PhC6H4, m-FC6H4 naphthyl, benzothiophene Yield 87 to 99% ee 82 to 91%

Scheme 22 Asymmetric arylation of the substituted 3aryloxindoles 83 with 2,4-dinitrofluorobenzene 80

4.2 1,1’-Binaphathyl based [7.7] P-spiro tetraarylaminophosphonium salts With the success achieved using tetraaminophosphonium backbone, Ooi and coworkers further thought to replace the amino acid derived backbone with a chiral binaphthyl di-amine unit. It was assumed that introduction of aromatic amines on the phosphonium center would contribute in increasing the acidity of N-H protons, which eventually enable them to interact with the electronically neutral substrates[38]. The catalyst

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[7.7]-P-spirocyclic arylaminophosphonium core 87 with barfates ([3,5-(CF 3 ) 2 C 6 H 3 ] 4 B−) as the counter ion, was synthesized in two steps from 3,3’-diphenyl(R)-2,2’-diamino-1,1’-binaphthyldiamine 85 and (S)2,2’-diamino-1,1’-binaphthyldiamine (BINAM), followed by an anion replacement from chloride to barfates (Scheme 23). Ar NH2

(R)

NH2

PCl5 toluene rt-50 oC

(S) or (R) BINAM o

110 C

(R)

Ar

Ar Cl H H N N P N N H H

Table 6 Effect of structure of arylamine 90 and catalyst 88a and 88b on yield and ee of 91 Ar H N ( R)

Ar H N

H N

N H Ar

Ar

BArF

BArF = [3,5 (CF3)2-C6H3]4B

86

(R)

89

BArF H N

P N H

(S/R)

N H

87

of

binaphthyl

90

catalyst 88.BArF NHAr1 (2 mol%) NO2 Ph toluene 0 oC, time 91

Catalyst Ar1 Time Yield ee (H or Ar) (h) (%) (%) 1 88a.BArF 4-MeO 23 37 19 (H) -C 6 H 4 2 88a.BArF 2,4-(MeO) 2 - 23 42 41 (H) C6H3 3 88a.BArF 2,4-(MeO) 2 - 23 86 61 (Ph) C6H3 4 88b.BArF 2,4-(MeO) 2 - 27 87 83 (Ph) C6H3 5 88b.BArF 2,4-(MeO) 2 - 11 98 94 (3,4,5-F 3 C6H3 C6H2) 6b 88b.BArF 2,4-(MeO) 2 - 12 98 95 (3,4,5-F 3 C6H3 C6H2) a Reaction performed on 89 (0.1 mmol) scale with 2 equiv. of 90 in toluene (1mL). bReaction was conducted at -15 °C. Entry

Ar

Scheme 23 Synthesis tetraaminophosphonium core

NO2 + Ar1NH 2

Ph NaBArF THF

Ar

BArF

-

Ar

H N

N H

88b.BArF

88a.BArF (S/R)

(S)

P N H

N H

Ar = Ph

85

H N

( R) ( R)

P

based

After obtaining a homochiral unit 88.BArF, they employed the catalyst for a reaction between nitrostyrene 89 and arylamines 90 (Table 6)[39]. The increased electron density on 90 (with the help of an additional methoxy group) improved the ee from 19 to 41% (entry 1 and 2) in the presence of catalyst 88a.BArF(H). They further realized that introduction of an unsubstituted phenyl ring on catalyst 88a.BArF at 3,3’-position of binaphthyl ring is beneficial, as it improved the yield and ee (entry 3). Surprising improvement in the yield and ee (87% yield and 83% ee) was observed when the opposite enantiomer 88b.BArF was used in the reaction. The key difference in both structures of 88a and 88b is the orientation of the diaminobinaphthyl rings, which are occupying almost perpendicular position to each other in 88b, allowing an easy facial discrimination for hydrogen bonding with 89. Replacing the unsubstituted phenyl ring with an electron withdrawing phenyl ring (3,4,5-F 3 C 6 H 2 ) further improved the ee to 94% and also caused a decrease in the reaction time. The scope of reaction was investigated using ortho-, meta- and para-electron donating, withdrawing groups, fused aromatics, heterocycles and alkyl groups on 92. All these substituents produced the corresponding β-arylamino nitroalkane 94 with excellent yields (89 to 99%) and ee (86 to 97%) (Scheme 24). The catalyst 88b.HBArF (Ar = Ph) was also found to be applicable in the sulfa-Michael addition of thiophenol 95 to nitrostyrene 89 and formed the

NO2

R

MeO

OMe

+ NH2

92

88b.BArF (2 mol%) toluene -15 oC

93

R = 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H3, 4-Me-C6H4, 3-MeO-C6H4, 3-BrC6H4, 2-F-C6H4, 1-napthyl, 2-naphthyl, 3-furyl, Me2CHCH2, Me(CH2)4

MeO

OMe

HN NO2

R

94 Yield 89 to 99% ee 86 to 97%

Scheme 24 Scope of nitroolefin in 88b.BArF-catalysed Aza-Michael reaction

product with 77% yield but strictly in presence of a base, (Table 7, entry 1 to 3)[40]. Under the same reaction condition, the catalyst 88a.HBArF (Ar = Ph) displayed an improved yield (88%) with an enantioselectivity of 66.5%. They further modified the catalyst 88a.HBArF by introducing 3,4,5trifluoroaryl group at the 3, and 3’-position of catalyst 88a.HBArF, which improved the enantioselectivity slightly to 74.3 % (with 95% yield) with decrease in reaction time. The contribution from electron donating methoxy groups on the thiophenol ring 95

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10.1002/adsc.201700795

Advanced Synthesis & Catalysis

Table 7 Effect of catalyst structure on the addition of thiophenol 95 to nitrostyrene 89 NO2

Ph

Ar

+

89

SH

88a and 88b.HBArF (2 mol%)

Ar

toluene -40 oC

95

S NO2

R

96a to 96c

95a Ar = 4-MeO-C6H4, 95b Ar = 2,4-(MeO)2-C6H4, 95c Ar = 3,4-(MeO)2-C6H3

Entry Catalyst Base (mol%) thiophenol Time Yield % ee ratio 1 88b.HBArF 95a 26 trace 2 88b.HBArF 2,6-lutidine (1) 95a 26 77 53.0:47.0 3 2,6-lutidine (1) 95a 42 17 4 88a.HBArF 2,6-lutidine (1) 95a 26 88 66.5:33.5 5b 88a.HBArF 2,6-lutidine (1) 95a 8 95 74.6:25.4 6 88a.HBArF 2,6-lutidine (1) 95b 12 99 74.3:25.7 7 88a.HBArF 2,6-lutidine (1) 95c 9 99 97.2:2.8 8 88a.HBArF 2,6-lutidine (0.5) 95c 5 99 97.8:2.2 a Reaction condition: 89 (0.1 mmol), 0.11 mmol of 95, 1 mol% of 2,6-lutidine and 1 mol% of 88a or 88b.HBArF in toluene (5.0 mL) at -40 °C. Absolute configuration of products 96a and 96c were determined to be S, determined by X-ray diffraction analysis, and that of 96b was assigned by analogy. bCatalyst carrying 3,4,5-trifluoroaryl group at 3 and 3’ position.

(entry 5 to 7) was essential to achieve the highest yield 99% with excellent enantioselectivity of 97.2%, though the position of the electron donating groups on thiophenol ring also played a major role in obtaining high enantioselectivity. They proposed that the difference in the three-dimensional structure of the catalysts probably generating an interaction between the 2,6-lutidine and thiophenol 95a. Addition of 3,4-dimethoxythiophenol 95c to the nitroolefins 92 carrying electron-withdrawing and donating groups at different positions on aryl ring displayed quantitative yields and excellent ee (Scheme 25). Substituent’s position on the aryl ring and their electronic nature did not affected the yields and ee. NO2

R

88a.HBArF (2 mol%) MeO 95c, toluene

OMe

-40 oC 92

S

97 R

R = 2-F-C6H4, 2-MeC6H4,3-BrC6H4, 3-MeOC6H4, 4-FC6H4, 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 1-naphthyl, 3-furyl, Me(CH2)4, Me2CH, cyclo-hexyl, t-BuCOO(CH2)4, t-BuMe2SiO(CH2)3

NO2

Yield 97 to 99% ee 94.8 to 98.4%

Scheme 25 Substituent’s effect of different nitroolefins 92 on asymmetric addition of 3,4-dimethoxythiophenol 95c

Recently, Ooi and co-workers used ‘synergy’ between P-spiro chiral arylaminophosphonium barfates 98.HBArF and transition metal photosensitizer such as Iridium (Ir) for radical induced asymmetric coupling of Narylaminomethanes 99 with aldimines 100 (Scheme

98.HBArF N

Hydrogen bond donor (4 mol%) N Ph 101 [Ir(ppy)2(L)]BArF (1 mol%) Ph

Ms

+ H

Ph

99

H

visible light toluene, rt, 8 h

100

HN Ph

Ms NPh2

* 102

Ar H N

H N P

N H

N H

Ar

BArF

98.HBArF

98a Ar = Ph, Yield 56%, ee 53% 98b Ar = 2-PhC6H4, Yield 79%, ee 89 % 98c Ar = 2-Ph-4-CF3C6H3, Yield 89%, ee 94% BArF = [3,5 (CF3)2C6H3]4B

Scheme 26 Effect of reaction components on synergistic catalysis The reactions were performed with 0.20 mmol of 99 and 0.10 mmol of Ph 2 NMe 100 with hydrogen bond donor (4.0 mol%) and 84 (1.0 mol%) in 0.5 mL of toluene at ambient temperature for 8 h under argon atmosphere with visible light irradiation (15 W white LED).

26)[41]. The reaction essentially proceeds with three basic components, namely, a hydrogen bond donor, a photosensitizer and visible light. However, the ligand attached to the Ir center, photosensitizer and hydrogen bond donor mainly drives the reaction performance. They tested several combinations of ligands (such as 2,2'-bipyridine, 1,10 phenanthroline, and 2,9-dimethyl-1,10-phenanthroline (Me 2 Phen)) in synergy with various of hydrogen bond donors viz. phosphoric acid, benzoic acid, 3,3’-Ph 2 -BINOL, thiourea, tetrabutyl ammonium barfates (Bu 4 N+.BArF¯), 2,6-lutidine·HBArF and achiral tetraaminophosphonium barfates(4CF 3 C 6 H 4 NH) 4 P+.BArF¯).

15 This article is protected by copyright. All rights reserved.

10.1002/adsc.201700795

Advanced Synthesis & Catalysis

NHMs

MsHN

Ar' Ar' pinacol coupling N Ar1

N

Ms

Ar1

II

NMePh Friedel-craft Ms HN NPh2 Ar1 *

radical coupling

III

[*Ir ]

III

[Ir ] BArF

NPh2 H

NH HN P NH NH *

H

[Ir ]

H

Ar1

BArF * III

NPh2

imine amine

Ms

[Ir ]

Ms

HN

BArF

visible light irradiation

BArF

* NH HN P NH Ms N NH * P-Im Ar B.HBArF

NPh2

B

Figure 8 Working hypothesis for synergic phosphonium salt catalysis

These combinations either failed to initiate the reaction or they formed the product in low yields. Meanwhile, with the positively charged hydrogen bond donors, the reaction yield was found boosted with the formation of racemic product. Using P-spiro chiral arylaminophosphonium barfates 98a.HBArF as a hydrogen bond donor, in synergy with 2,9-dimethyl1,10-phenanthroline (Me 2 Phen) gave the product with ee of 53% (56% yield). They further improved the product yield and ee by manipulating the electronic property of the hydrogen bond donor, by means of replacing the phenyl group on 98a.HBArF with 2phenyl-4-trifluoromethylphenyl substituent (98c.HBArF). They hypothesized a possible mechanism for the product formation, which is depicted in Figure 8. In the reaction, the radical initiation takes place through the reversible excitation of Ir complex from Ir(II) to Ir(III), by visible light irradiation, subsequent quenching of this excited Ir(III) complex with the Ph 2 NMe generates a Ph 2 NMe radical stabilized by negatively charged barfates and Ir(II). The Ir(II) further transfers an electron to imine to form an anionic radical stabilized with cationic Ir(III) complex, followed by an Ir ion exchange with aminophosphonium ion to generate anionic radical and cationic aminophosphonium ion-couple. This ion couple then undergoes a radial reaction with diphenyl amino methyl radical to yield 1-2 diamine derivative. It is important to mention that in absence of photosensitizer Friedel-Craft-type adduct formed, whereas removing the hydrogen bond donor from reaction yielded Pinnacol coupling product, shows the significance of synergic behavior of the reaction components. This synergic catalyst-ion pair accommodated a wide substrate range, regardless of substrate or its substituents electronic properties and substitution

pattern and displayed moderate to good yields with excellent enantioselectivities (Table 8, entry 1 to 7). Certain decreases in the yields of heteroatomic and fused aromatics were observed (entry 8 and 9). Different amino methyl substituents also showed comparable yields and enantioselectivities (10 to 16). Table 8 Substrate scope with different aldimines 103 and substituted methylamine 104. N Ar1

R

Ms

N

+ H

103

Entry Ar’

98c. HBArF (4mol%) R'

H

Me2Phen (1mol%) visible light toluene, rt, 8 h

NH

R N

Ar'

R'

105

104

R

Ms

R’

Yield ee (%) (%) 1 4-MeC 6 H 4 Ph Ph 85 97 2 4-FC 6 H 4 Ph Ph 90 91 3 4-ClC 6 H 4 Ph Ph 85 91 4 4-MeSC 6 H 4 Ph Ph 72 96 5 3-MeC 6 H 4 Ph Ph 75 90 6 3-MeOC 6 H 4 Ph Ph 75 85 7 2-MeC 6 H 4 Ph Ph 77 94 8 2-Naphthyl Ph Ph 64 94 9b 3-Thiophenyl Ph Ph 60 95 10 Ph 2-Naphthyl Ph 82 93 11 Ph 3-thiophenyl Ph 83 91 12 Ph 4-MeC 6 H 4 4-ClC 6 H 4 85 89 13 Ph 4-BrC 6 H 4 4-BrC 6 H 4 63 92 14 Ph iPr Ph 73 91 15 4-MeC 6 H 4 iPr Ph 83 94 16 4-MeC 6 H 4 n-Hex Ph 65 91 a Reactions were performed with 0.20 mmol of 103 and 0.10 mmol of RR’NMe 104 with catalyst 98c (4.0 mol%) and ligand Ph 2 NMe (1.0 mol%) in 0.5 mL of toluene under argon atmosphere with visible light irradiation (15 W white LED). b2.0 mL of toluene was used as solvent.

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Advanced Synthesis & Catalysis

Using a similar chiral aryl backbone, i.e. [7.7]-spiro cyclic phosphonium salt with bromide as a counter ion 106 Ma et al. investigated the base free amination of benzofuran-2(3H)-ones 107 using (E)-dibenzylazene1,2-dicarboylate 108 (Scheme 27)[42]. The corresponding catalysts were prepared through simple refluxing of (S)-4-5-disubstituted 2,2’bis(bromomethyl)-1,1’-binaphthyls with (S)-4,5dihydro-3H-dinaphtho[2,1-c:1’,2’-e] phosphepine in toluene. Asymmetric addition of 107 to 108 achieved smoothly in presence of catalyst 106a to form product with a moderate ee (Scheme 27). BnO2CN=NCO2Bn 108 catalyst 106

Ph H O O

107 R

P Br R

106

o toluene, 25 C, 48 h

R1

R2 H

R2

BnO2C O

N

+

N

O

110

CO2Bn

Ph

Scheme 27 Screening of novel quaternary phosphonium salts 106 for asymmetric amination of 3-phenylbenzofuran2-(3H)-one 107

An addition of bulky electron withdrawing substituent at 3,3’-position on catalyst 106c improved the yield as well as ee up to 95%. Additional advancement in the catalyst structure was made by means of introducing another tier of trifluoroaryl ring to yield catalyst 106e, which contributed effectively in raising the yield up to 99%, with an outstanding ee (98%). Changing the solvent as well as lowering the catalyst loading declined the yield and ee. The scope of the reaction was investigated using catalyst 106e (Scheme 28). The benzofuranone carrying electron-donating and electronically neutral substituents 110 formed the product 111 in high yields and ee (90-98%) (111a-c). In contrast, the electron withdrawing groups on 110 displayed a lower ee (111d-e); though the product yield in these reactions remained virtually unaffected. On the other hand, the substituents on the aryl ring (R2) of 110 did not alter the yield and ee of the product (111f-i) by any means. Ma et al. used the same catalysts 106a to f for asymmetric fluorination of the 3-sustituted bezofuran2(3H)-ones 110 using N-fluorobis (benzenesulfonimide) (NFSI) 112 as a fluorine source (Scheme 29)[43]. In the investigation, they performed several experiments by changing the reaction parameters, such as temperature, solvents, bases,

N CO2Bn

N CO2Bn

O

O

O

O O

O

111a, yield 99%, ee 98%

111c, yield 94%, ee 98%

111b, yield 96%, ee 90%

N CO2Bn

Cl

HN CO2Bn

HN CO2Bn

N CO2Bn

N CO2Bn

Br

O

N CO2Bn

106a R = H, Yield 39%. ee 66% 106b R = Ph, Yield 85%, ee 65% 106c R = 3,4,5-F3C6H2, Yield 80%, ee 95% 106d R = 3,5-(CF3)C6H3, Yield 80%, ee 90% 106e R = 3.5-(3,4,5-F3C6H2)2C6H3, Yield 99%, ee 98% 106f R = 3.5-(3,5-(CF3)2C6H2)C6H3, Yield 87%, ee 95%

HN CO2Bn

HN CO2Bn

O

O

O

O

O

111

HN CO2Bn

O

O

O

111e, yield 99%, ee 76%

111d, yield 99%, ee 81%

109

O

toluene, 25 oC, 48 h

HN CO2Bn

HN CO2Bn

N CO2Bn

106e (2 mol%)

108

N CO2Bn

HN CO2Bn

Br

Cl

F

111f, yield 94%, ee 98%

HN CO2Bn

HN CO2Bn

HN CO2Bn

N CO2Bn

N CO2Bn

N CO2Bn O

O

O

O

O

O

111g, yield 92%, ee 99%

111h, yield 97%, ee 99%

111i, yield 99%, ee 97%

Scheme 28 Catalytic enantioselective amination of 3substituted benzofuran-2(3H)-ones 110 R2

R1

F O

+

PhO2S

N

SO2Ph

O

110

112

R1 = MeO, Me, Cl, Br, R2 = Bn, p-MeBn, p-MeOBn, p-BrBn, p-ClBn, p-FBn, m-BrBn, o-BrBn, p-FC H 6 4, p-ClC6H4, p-BrC6H4

106e (2 mol%)

R1

toluene (0.33 M), 50% aq. K2HPO4 (0.1 ML) 25 oC, 12 h

F R2 O O

113

Yield 91-97% ee 9-56%

Scheme 29 Asymmetric fluorination of substituted benzofuran-2(3H)-ones 110

phase of the base (solid and aqueous), its concentration and equivalents. Unfortunately, none of these attempts were successful. Finally, the best results were only obtained when 50% aqueous K 2 HPO 4 was used under liquid-liquid phase transfer condition with catalyst 106e to form the fluorinated product in 93% yield and 50% ee. They expanded the scope of reaction by using the optimized reaction condition. Finally, with the help of substrate contribution, the highest ee achieved was 56% with R2 group bearing para-fluorobenzoyl group. Changing the position of fluorine atom on the benzyl ring also dropped the ee. In another reaction, where benzofuranone 110 possesses R2 as a para-bromo phenyl group (instead benzyl group) dropped the ee (9%) to the lowest value, highlighting the importance of stearic contribution made by benzyl group.

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Advanced Synthesis & Catalysis

5. Amino acid derived phosphonium salts as asymmetric catalysts Chiral amino acids are abundant in nature and known for many years, but their use in asymmetric catalysis was limited. As most of the asymmetric catalyst designed in the past few decades were sourced only from (S)-proline[44]. But from 2000 onwards, considerable attention to other amino acids such as phenylalanine, tryptophan, threonine and valine have been given and number of synthetic methods were developed[45]. Although in these studies, the direct use of amino acid as an asymmetric catalyst is not recommended due to their narrow applicability scope. Rather modification in the basic amino acid structure is suggested via introducing metals or amine, urea, thiourea and phosphine to achieve a high product enantioselectivity[46]. The newly added functional group and chiral backbone of the amino acid contribute co-operatively to improve the overall efficiency of the catalyst by providing sites for hydrogen bonding and electrostatic interaction.

118 (5 mol%) KOH (5 eq.) o toulene, -20 C

NHBOC CH3NO2 SO2Ph

Ph

Ar1

119

Bn N H

Bn

O Ar1

Br PPh3

Bn

S Ar1

N H

N H

Br PPh2Bn

118d, Yield 71%, ee 89%

OH + NH2

114

Ar1

1. K2CO3,MeOH Cl 2a. PPh3/CBr4, DCM

2b. PR3, reflux 115

H N

Ar1 O

PR3Br R

N H

N H

Ar1 = 3,5 (CF3)2C6H3 R = alkyl or aryl

Scheme 30 Synthesis of amino acid derived bifunctional phosphonium salts

These bifunctional catalysts essentially consist of two functionalities i.e. amide hydrogen and phosphonium ion, which virtually interact with the substrate to decide the stereo chemical outcome of reaction. Zhao et al. prepared several catalysts using (S)-phenyl alanine, (S)-isoleucine and other amino acids for azaHenry reaction, between N-boc imine 117 (generated in situ from amidosulfone) and nitromethane 11 (Scheme 31)[47]. Catalyst 118d with urea functionality showed a better ee than the catalyst with amide functionality (118a to c). The catalyst 118d with thiourea functionality performed even better and displayed an excellent ee (89%). The improved performance of urea-based catalysts was credited to the additional hydrogen-bonding site in urea.

Br PPh2Bn

118e, Yield 83%, ee 92%

N H

N H

Br PPh2Bn

118f, Yield 68%, ee 96%

R S S Ar1

N H

N H

N H

Y PPh2Bn

N H

Br PPh2Bn

118i, R = H, Yield 83%,ee 93% 118j, R = p-OMe, Yjeld 79%, ee 96% 118K,R = p-F, Yield 68%, ee 95%

MeO

S N H

Br PPh2R Br

R=

118l, Yield 71%, ee 96%

side chain

116

S Ar1

N H

O

118c,Yield 98%, ee 74%

Ph

S Ar1

hydrogen bonding

R

Br PPh2Bn

Ar1 = 3,5-bis(trifluoromethyl)phenyl

Zhao et al. in 2013 reported the first amino acid based bifunctional phosphonium salt 116 obtained from (S)2-amino-3-phenylpropan-1-ol 114 in two simple subsequent steps (Scheme 30).

for ion pair formation

N H

N H

Br PPh2Bn

118b , Yield 64%, ee 43%

118a, Yield 75%, ee -16%

Bn

O Ar1

N H

118g Y = Br, Yield 75, ee 95% 118h Y = Cl, Yield 75, ee 95%

5.1 Bifunctional phosphonium salts

NO2

Ph

11

117 O

NHBoc

118m, Yield 75%, ee 96%

Scheme 31 Chiral phosphonium salts for asymmetric addition of nitromethane 11 to N-boc amidosulphone 117 in presence of bifunctional catalysts

Interestingly, catalyst 118b carrying a benzyl group with two phenyl rings on the phosphonium ion displayed a better and improved ee than 118a. Changing the amino acid backbone from phenylalanine to isoleucine (118e and 118f) improved the ee slightly to 96%. The isoleucine-derived catalyst 118j with an aryl group on thiourea, carrying electrondonating group displayed the highest ee of 96% with 79% product yield. Catalyst 118j under an optimized reaction condition gave good to excellent yields and ee for various amidosulphone 120 carrying different electron-donating and withdrawing groups (Scheme 32). The presence of phosphonium ion and two hydrogens on thiourea segment of bifunctional catalyst are crucial in order to get the product in high yield and excellent ee, respectively (Figure 9). The simultaneous contribution from both the functionalities is essential, as missing one of them resulted in poor performance of the catalyst.

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Advanced Synthesis & Catalysis

118j NHBoc

+ CH3NO2

o toluene, -20 C 5h

SO2Ph

R

NHBoc

KOH (5 equiv.)

NO2

R

O

11

120

Table 9 Catalyst screening of 118a and 123a to i for asymmetric addition of 3-phenyloxindole 63 to methyl vinyl ketone 105

121

R = p-FC6H4, p-ClC6H4 p-BrC6H4, p-MeC6H4, p-MeOC6H4, p-CF3C6H4 p-NO2C6H4, m-ClC6H4, o-FC H cyclohexyl, 6 4, 2-thienyl

123 (10 mol%) base (5 equiv)

N

124

Ph

Br

Br

Br

PPh3

PPh3

P(n-Bu)3

O

HN

Bn

PPh2Bn

118n, Yield 83%, ee 5%

F3C

N H

N H

Ar

Ar

118a

123a

123b

118o, Yield 20%, ee 13%

Figure 9 Controlled experiment results in support of cooperative catalysis of bifunctional catalysis

HN

O

O

123c

123e Br PPh3

O

HN

O Ar

123d

PPh3 HN

HN

Ar

Ar

Br

Encouraged by the results obtained on catalyst 118j, they further employed different amino acid derived bifunctional phosphonium salts for asymmetric addition of 3-phenyloxindole 63 to methyl vinyl ketone (MVK) 122 (Table 9)[48]. To serve the purpose, they designed several catalysts using three different approaches, (a) changing groups on phosphonium ion (123a-d), (b) changing the counter anion from bromine to iodine (123a and 123d) (c) changing groups on amino acid backbone (123e to i). Upon screening these catalysts, they revealed that the catalysts with three phenyl rings on phosphonium ion performed much better than aliphatic and diphenyl phosphonium salts. Changing the counter ion from bromine to iodine lowered the yield and enantioselectivity. Among the various amino acid backbones, only the isoleucine-derived catalysts 123a and 123i showed the highest ee. Dropping the reaction temperature and replacing the base from potassium acetate (KOAc) to potassium carbonate (K 2 CO 3 ) improved the ee to the highest 89% with catalyst 123a. Toluene was the most suitable solvent for the reaction, as solvent change from toluene to chloroform and then ether dropped the ee considerably. Catalyst 123a was further utilized in asymmetric Michael addition of 125 to 122 and acrolein 64 (Scheme 32). In comparison, the reaction times for 122 were longer than 64. Additionally, electron-donating groups on the oxindole moiety furnished the product in good yields and high ee with both the substrates (122 and 64), but

PPh3

PPh2Bn

PPh2Et HN

I

Br

Br

PPh2

O

Ar

Bn

S Br

HN

O

CF3

N

Boc

63

CF3

N H

O N

solvent, Temp, 10-20 h

Boc

HN

F3C

Ph

Ph O

Scheme 32 Asymmetric addition of nitromethane 11 to Nboc protected amidosulphone 120 in presence of catalyst 118j

S

O

122

Yield 77 to 98% ee 88 to 98%

Br

Ph

PPh3 HN

O

O Ar

CF3

Ar 123g

123f

123h

Br PPh3 HN

O

Ar = (CF3)2C6H3

Ar

123i

Entry Catalyst Solvent Base

Temperat Yield ee -ure °C) (%) (%) 1 118a toluene K 2 CO 3 -70 89 66 2 123a toluene KOAc -45 99 79 3 123b toluene KOAc -45 99 52 4 123c toluene K 2 CO 3 -70 99 21 5 123d toluene K 2 CO 3 -70 99 24 6 123e toluene KOAc -45 85 39 7 123f toluene KOAc -45 99 70 8 123a toluene K 2 CO 3 -70 99 89 9 123g toluene K 2 CO 3 -70 99 83 10 123h toluene K 2 CO 3 -70 99 81 11 123i toluene K 2 CO 3 -70 99 88 a Reaction conditions: 63 (0.1mmol), 122 (0.12mmol), 123 (0.01 mmol) and base (5 equiv.) in solvent (0.2 mL)

the electron-withdrawing groups showed a negative effect and caused a decrease in the yield of both. The more acidic nature of 3-aryloxindole (R = F, Ar = Ph), tempted them to use bulkier and weaker base like

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10.1002/adsc.201700795

Advanced Synthesis & Catalysis

potassium benzoate to avoid the side reactions.

Table 10 Effect of catalysts structure on the asymmetric addition of diphenyl malonate 128 addition to p-QMs 129 O

O

K2CO3 123a O (10 mol%) R o toluene, 70 C

Ph R O

+

N

125

OPh

O

129

126

1. K2CO3 (5 equiv.) 123a O (10 mol%) R o toluene, 70 C

N

R

125

PPh3

PPh3

CF3

O

F3C

F3C

CF3

CF3

N

130c

130b

Boc

118a R = Bn 123a R = s-Bu 123g R = i-Pr 123h R = Ph 130a R = CH3

127

Ph Ph NH

O

F3C

NH

CF3

O

P Ph

Boc O

N

NH Ph O

CF3 CF3

Figure 10 Proposed transition state for asymmetric addition of 3-aryl indole 125 to methyl vinyl ketone 122

For the addition of 125 to 122, the use of phosphonium salt 123i (yield 99% with 85% ee in 10h) was found to be beneficial compared to its corresponding phosphine structural counterpart, since it reduced the reaction time significantly, while displaying almost similar yield and ee (yield 92% and ee 88%, 72h). Recently, Zhao and co-workers utilized bifunctional phosphonium salts for asymmetric addition of different malonates to para-Quino Methides (p-QM) 129 (Table 10)[50]. The catalysts 118a, 123a, g, and h used previously in aza-Henry reaction and Michael addition showed poor ee (Table 11), except the phenyl

NH

S

Br

Ph

NH

S

NH

CF3

Br P(p-tolyl)3

Ph

PPh2Bn

F3C

130e

Br Ph

PPh2 NH

S

PPh2

130d

Formation of product in the presence of bifunctional catalyst is claimed to appear through the transition state (Figure 10) in the similar manner reported by Liu et al.[49] for phosphine based organocatalysts. In their suggested transition state, the phosphonium center and amide hydrogen interacts with the enolate of oxindole 63, whereas subsequent charge reversal causes the nucleophilic Michael addition to MVK through the opposite side of amino acid backbone. Ph

PPh3 NH

O

Scheme 32 Michael addition of substituted 3-aryloxindoles 125 to MVK 122 and acrolien 64 in presence of catalyst 123a

Ph

Br Ph

NH

O

NH

O

Yield 80 to 91% ee 75 to 94%

R = H, CH3, MeO

Br

Ph

2. Wittig reaction R3PCHCOOEt (126) 6 to 8 h 64

Boc

131

Br

COOEt

+

COOPh COOPh

Boc

R = H, CH3, MeO

O

3 equi. of K2CO3 o toulene, -40 C, time

128

Yield 99% ee 80-89%

R

Catalyst

N

122

Ph

OH

O

PhO

Ph

10 to 72 h

Boc

O

O

PPh2Bn NH

NH

F3C F3C

CF3

F3C

130g

130f

Entry

CF3

CF3

130h

Catalyst

Temperature Yield ee (%) (°C) (%) 1 118a -40 65 28 2 123a −40 86 53 3 123g −40 70 37 4 123h −40 98 95 5 130a −40 93 40 6 130b −40 91 -14 7 130c −40 79 57 8 130d −40 31 50 9 130e −40 23 47 10 130f −40 90 85 11 130g −40 90 89 12 130h −40 65 28 a p-QM 128 (0.24 mmol), 129 (0.20 mmol), bifunctional catalyst (10 mol%) and K 2 CO 3 (3 equiv.) in toluene (1 mL) at −40 °C.

glycine derived catalyst 123h. This motivated them to examine the effect of different phenyl glycine derived phosphines, phosphonium salts and urea functionalities (130b to 130h) on the reaction outcome. However, these modifications did not gave the expected results and displayed lower yields and ee (than catalyst 123h). Although, thiourea modified dual hydrogen bond donor catalysts 130f and 130g were impressive as it displayed slightly lower ee than 123h. Any changes in the catalyst functionalities of 123h, such as, at phosphonium center or at bis-3-5-

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10.1002/adsc.201700795

Advanced Synthesis & Catalysis

(trifluoromethyl)benzamide moiety dropped ee and yields. The yield and ee were also found to be sensitive to reaction temperature and catalyst loading (mol% in the reaction). They further investigated the scope of catalyst 123h for diphenyl malonate 128 addition to different substituted p-QM 132 (Table 11). Table 11 Scope of asymmetric 1,6-addition of p-QMs 132 with diphenyl malonate 128 catalysed 123h O

OH

tBu

tBu

O

123h (5 mol%)

O

+ PhO

tBu

tBu

OPh K CO (3 equiv) 2 3

o Toluene, -40 C Ar2

Ar2

COOPh COOPh

132

128

No.

R

OH

R1 = Cl R1 = Br R1 = CF 3 R1 = CN R1 = MeO

COOPh COOPh

R1

OH

2

133

Ar2

1

Time Yield (h) (%) 22 94 24 97 12 98 14 93 86 96

2

COOPh

ee (%) 90 94 94 90 88

R = CH 3 R2 = MeO R2 = Cl R2 = Br

28 28 12 14

96 99 97 95

96 97 97 96

R3 = Cl R3 = CH 3 R3 = MeO

72 88 12

93 92 97

73 85 67

COOPh R2

OH

3

reactive than ortho-methides. Especially metasubstituted methides gave outstanding yields and ee. Difference in the reactivity also observed among the electron-withdrawing and donating methides, as electron-withdrawing methides reacted faster than electron-donating methides, although with both substituents high yields and ee were observed. Heterocyclic and bulky aromatic substituents also provided high yields and ee (entry 4). Replacing the bulkier tert-butyl group on 132 with i-Pr and Me group showed a drop in ee (entry 5). To examine the stearic effect of malonate esters, Me, Et and Bn malonates were reacted with 4-BrC 6 H 4 para-QM 134, amongst diethyl malonate 135 gave an excellent yield and ee (92%). EtOOC

O

R4

96

88

85

100 90

92 95

90 93

134

136 Yield and ee 92%

Scheme 33 Reaction of para-bromo methide 134 with diethyl malonate 135 in presence of catalyst 123h

A Bifunctional catalyst 137 also used in the aziridine 138 ring opening reaction with aromatic thiols 139 as a nucleophile (Scheme 34). O

OH

R5 : Ph, R6: iPr, R7 : iPr R5 : Ph, COOPh R5 R6: Me, COOPh R7 : t-Bu R5 : Me, R6: t-Bu, R7 : t-Bu a Reaction condition 0.1 mmol of 132, mol% of catalyst 123h 5

R6

R7

N H

CF3

6

12

6

93

92

96

84

75

56

0.15 mmol 128, 5

Substituents electronic nature and position on the phenyl ring of 132 affected the yield and ee both. Among different aryl substituted methides 132, the para- and meta-substituted methides were more

Br PPh2Bn

137 NHR

N

Ts

+

ArSH

n

COOPh

COOEt

Br

Br

F3C

R4= thiophene R4 = furan R4 = COOPh naphthyl

COOEt

o Toulene, -60 C

COOPh

OH

4

OH

135 123h (5 mol%), K2CO3

COOPh R3

COOEt

138

139

(5 mol%) CCl4, -10 oC K2HPO4

Ar = Ph Ar = 2-BrC6H4 Ar = 3-BrC6H4 Ar = 4-BrC6H4 Ar = 4-CH3OC6H4

n

SAr

140 Yield 83%, ee 59% Yield 90%, ee 62% Yield 94%, ee 70% Yield 94%, ee 67% Yield 80%, ee 57%

Scheme 34 Effect of substituted aromatic thiols 138 on yield and ee of amine 140

The chiral amine 140 obtained in excellent yields and with moderate ee. The aromatic thiol with electronwithdrawing groups furnished the product with slightly higher ee than thiol with electron-donating group. Among the electron withdrawing groups also, the group on meta-position exhibited slightly higher ee than ortho- and para-substituted aromatic thiols.

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Advanced Synthesis & Catalysis

5.2 Multifunctional phosphonium salts To expand the applicability of amino acid derived phosphonium salts, Zhao et al. introduced additional amino acid to the bifunctional catalyst to yield a dipeptide core. The synthesis of dipeptide core with multiple functional groups was achieved over four steps using chiral amino acids (Scheme 35). O R1

PPh2

R2

NH2

HBTU, DIPEA OH

+

R2

NHBoc

DCM

N H

NH

O

MeO2C

+ Ph

3

145

144

COOMe

(a) K2CO3 (2 equiv) o mesitylene, 0 C o (b) DMF, 0 C

Ph O

147

PPh2

Bn

O

O

1. TFA, DCM 2. Ar1NCX (X = O or S)

tunable depeptide backbone

R1

O R2

Ar1

Br

COOMe

Bn

O

142

141

X

146 Catalyst

O

MeO2C

R1

O

ee (146d and 146e). A further replacement of bis-3-5(trifluoro)benzyl group on phosphonium with a strong electron withdrawing group like p-nitrobenzyl group improved ee of the product to 95% (146f).

NH

Ar2CH2Br 110 oC

N H Ph

P Ph Ar2

NH

tunable H bond

PhCH3 N2

X

NH

Ar1

R1

O R2

S

N H

N H

NH

N H

Br P

Ph

S

Ph

NH

NH

Ph

Ar1

146b

Yield 83%, ee 49%,

Yield 86%, ee 69%,

PPh2

Bn

O Ar1

Ph

NH

Ar1

146a

Br P

Ph

tunable electronic and steric environment

S

143

The multifunctional PTC were initially employed for addition of methyl malonates 144 to (E)-6-bromo-1phenylhex-2-en-1-one 145 in S N 2 sequence to yield five or six membered ring 147, with a completely inverted stereo centers (Scheme 36)[51]. This particular reaction follows a two-step sequence; a) Michael addition of 144 to 145, b) nucleophilic displacement of bromine to yield five or six membered rings. The bifunctional catalysts that were previously employed in aza-Henry reaction gave low ee for 147. To improve the ee of 147, Zhao and co-workers prepared several dipeptides 146 using L-3-methyl valine, L-phenyl alanine, L-glycine and L-phenyl glycine. Amongst, a dipeptide derived from L-phenyl alanine and L-phenyl glycine bearing aryl ring (Ar1) as bis-3,5(trifluoromethyl)phenyl group on both the segments i.e. thiourea and phosphonium center, were found to be impressive as the ee was improved to 78% (catalyst 146c). Any changes (change in stereochemistry and removing the phenyl group) in the catalyst structure of 146c showed a negative effect and gave poor yield and

N H

NH

Ar1

Scheme 35 Synthetic route for amino acid derived multifunctional phosphonium salt 143

Introducing urea and dipeptide functionalities to bifunctional catalyst enables the option of additional structural tunability at R2 position. Moreover, it also offers two extra hydrogens for hydrogen bonding with the substrate. Besides that, it also provides a possibility to manipulate the electronic effects on catalyst structure.

Bn

O

NH

Ph S

Br P

Ph

Ph

P

Br Ph Ar1

146c

146d

Yield 84%, ee, 78%,

Yield 78%, ee -16%,

Ph O

NH

N H

Br Ph

Bn

O

Bn

O

Ar1

Ph

NH

Ar1

Ar1

NH

N H

NH

P

NH

Ph Ar1

NH

S Ar1

N H

Br Ph

P

Ph

NH

146e

146f

Yield 86%, ee 23%,

Yield 87%, ee 95%,

NO2

Ar1 = 3,5-(CF3)2-C6H3

Scheme 36 Asymmetric Michael addition of methyl malonate 126 to (E)-6-bromo-1-phenylhex-2-en-1-one 127 in presence of multifunctional catalysts 146

Change in malonate ester from Me to Et and Bn malonate caused a decrease in ee due to the increased steric hindrance. The catalyst 146f was found to be efficient in converting different 6-bromo conjugate enones to their corresponding products in high yields and excellent ee (Scheme 37). The different 6-bromo conjugate enones 148 with all substituents; irrespective of their electronic nature, type or position on aryl ring displayed high yields and excellent enantioselectivities to the product 149. The only discrepancy was noted with the substituents carrying strong electron withdrawing groups (4-CF 3 and 4NO 2 ), which only gave high ee when reaction temperature was lowered to −20 °C.

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Advanced Synthesis & Catalysis

MeO2C O

CO2Me

COOMe

catalyst 146f

Ar

n

CF3

COOMe

Br

F3C

1. K2CO3

o mesitylene, 0 C 2. DMF, 0 oC

148

n

Ar

H N

O

R'

O

Ph MeO

O H N

O

149

n=1 n=2

S

H N

Bn

O P MeO

Ar = Ph, 4-FC6H4, 4-ClC6H4 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 4-CF3C6H4 4-NO2C6H4, 2-naphthyl 2-thienyl, 3-ClC6H4, 2-ClC6H4

Ph

NO2

TS-i R'= Br(CH2)3

Scheme 37 Substrate scope for asymmetric addition of methyl malonate 144 to 6-bromo conjugate enone 148 in presence of catalyst 146f

The optimized reaction protocol was also found applicable to prepare chiral functionalized cyclohexane and chiral heterocycles 151, such as pyran 151a and piperidine 151b derivatives in excellent yields and good to excellent enantioselectivities using 7-bromo conjugate enones 150 as a starting material (Scheme 38). MeO2C

O X Ph

150

Br

Ph

Yield 82 to 93% ee 85 to 97%

Michael addition Re-face attack

Br

MeOOC

COOMe

SN2

O COOMe

Ar

COOMe

Intermediate

Ar O

147

Figure 11 Proposed transition state for bifunctional catalysts 146f

CO2Me

Catalyst 146f K (a) 2CO3 (2 equiv) mesitylene, MeOOC COOMe 0 oC Ph , (b) Cs2CO3 O DMF, 0 oC X 151 151a X= O, Yield 94%, ee 93% 151b X= NTs, Yield 90%, ee 82%

Scheme 38 Application of reaction in stereoselective synthesis of chiral heterocycles 151

In their proposed transition state (Figure 11), they claimed that the phosphonium center and its immediate amide hydrogen interact with the enolate (of malonate 144) through a hydrogen bond and with an electrostatic interaction, respectively. Whereas at the same time, thiourea moiety offer two of its hydrogens for hydrogen bonding with 6-bromo conjugate enone 145. The Michael addition of 144 takes place through Re-face due to the steric hindrance of phenyl and benzyl group of the catalyst to give an intermediate. The subsequent intramolecular nucleophilic displacement of bromo in S N 2 manner causes cyclization to yield the product 147. Amino acid derived multifunctional phosphonium salts are also found efficient in the tandem reaction between sterically hindered nucleophile like (E)-

trimethyl but-3-ene-1,1,4-tricarboxylate 152 and low reactive enones (chalcones) 153 (Scheme 39)[52]. Due to the failure of the bifunctional catalysts (118b, d, e, f, and g) in achieving high ee, they proposed to use the catalyst 146a possessing a dipeptide core. The catalyst 146a with an additional hydrogen-bonding site improved the ee to 77%. Replacing the benzyl group on phosphonium center of catalyst 146a with bis-3,5(trifluoromethyl)benzyl ring improved the ee to 88% (146c). However, it is noteworthy that the high diastereoselectivity (6:1) was only obtained with the catalyst 146a possessing tert-butyl group. They further prepared a catalyst 146b with a combination of both i.e. tert- butyl group on the amino acid backbone and bis-3,5-(trifluoromethyl)benzyl group on phosphonium center displayed 94% yield and a highest diastereomeric ratio with an excellent ee (95%). Any further changes in the catalyst structure and reaction condition (such as a change in base) dropped the yield and ee. The optimized catalyst was found to be excellent and to work with different malonates 156 (Me, Et and Bn) (Scheme 40). In addition, enones 157 having aromatic or heteroaromatic moieties also gave excellent yields, d.r. and ee. However, the same reaction protocol was not found suitable to form sixmembered ring with Cs 2 CO 3 , an attempt with increasing the base strength (NaOH) caused product racemization.

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10.1002/adsc.201700795

Advanced Synthesis & Catalysis

COOMe

O

O

MeOOC

152 +

R2

OMe

COOR1

o

Ph

-10 C, 24 h

O

R1OOC

Toluene -10 oC, 24 h

156

153

Br PPh2Bn

118b, Bn, Yield 90%, ee 15%, dr 1.5:1 R1

S N H

O

Br PPh2Bn

118d, R1= Bn = Yield 85%, eeb 34%, drc 2.2:1 118e, R1= Ph = Yield 76%, ee 3%, dr 1.2:1 118f, R1= t-Bu = Yield 90%, ee 30%, dr 1.6:1

HN Ph

Br

P

Ph

Ph

O Ph

Ph

Yield 94%, 6:1 d.r.b 95% ee

Yield 86%, 7:1 d.r. 96% ee

Yield 83%, 7:1 d.r. 96% ee O O

O

OMe

MeOOC MeOOC

MeOOC Ph

Ph

Br

Ar1 NH

Br

P

Ph

Ph

Br

Br

Yield 83%, 5:1 d.r. 92% ee

Yield 72%, 4:1 d.r. 93% ee

Yield 92%, 20:1 d.r. 94% ee

Ar1 S N H

O

146b, Yield 94%, ee 95%, dr 6:1 N H

MeOOC

OMe

MeOOC MeOOC Ph

S

Ph

O S

Bn NH

HN

Ar1 NH Ph

Ar1= 3,5-(CF3)2C6H3

OMe

O

O O

118g Yield 92%, ee 11%, dr 1.5:1

O

MeOOC

Br PPh2Bn

O

O

Ph

Bn

OMe

MeOOC

OMe

MeOOC

MeOOC

O HN

O

Ph

O

S NH

Ph

O

OMe

BnOOC BnOOC

EtOOC

Ph

Ar 146a, R2 = t-Bu, Ar = Ph Yield 90%, ee 77%, dr 6:1 146c, R2 = Ph, Ar = 3,5-(CF3)2C6H3 Yield 86%, ee 88%, dr 3.5:1 154a, R2 = H, Ar = 3,5-(CF3)2C6H3 Yield 78%, ee 84%, dr 1.2:1

OMe

EtOOC

MeOOC

Ar1 NH

O

O

OMe

MeOOC

Bn NH

N H

N H

O

S

R1=

Ar1

O

R3

158 R2

R1

O

Ar1

OMe

R2

OMe

155

O

R1OOC

146b (5 mol%) 1 R OOC Cs2CO3 (2 eq.)

O

Ph

Ar1

R3

157

R3

Toluene O

Ph

O

catalyst MeOOC OMe (5 mol%) MeOOC Cs2CO3 (2 equiv.)

P

Br Ph

Ar1

154b, Yield 96%, ee 86%, dr 5.5:1

Scheme 39 Asymmetric addition of (E)-trimethyl but-3ene- 1,1,4-tricarboxylate 152 to chalcone 153 a Reactions were carried out using 152 (0.1 mmol) and 153 (0.1 mmol) and catalyst (5 mol%) and Cs 2 CO 3 (2equiv) in toluene (1.5 mL) at −10 °C for 24 h.

The multifunctional phosphonium salt 146a was also found to be impressive in Michael addition of malonate 144 to enone 153 (Scheme 41)[53]. Prior to use multifunctional catalysts, they tested several bifunctional catalysts (118a, b, and c) but these catalysts failed to form the product with high enantioselectivity (yield >95%, ee 96%), but with moderate ee (19:1

N H

NH

Ph

Ar1

N H

NH

146e Yield 98%, ee 3% dr >19:1 Bn

O Br

Ph

P

O

NH

Ar1

O Ar1

NH

Ar1

Ph

Br O

Ph Ar1

NH

Bn

O

P

Ph

NH

Bn N H

Br P

Ph

159a Yield 95%, ee 53% dr 12:1

154b Yield 99%, ee 90% dr 15:1 O

N H

NH

Ph Ar1

Chiral phosphonium salt organocatalysis has recorded a noteworthy growth in the last decade (2007-2017), since several new phosphonium based asymmetric catalysts have been developed. Initial success was obtained using novel P-spiro chiral tetraaminophosphonium chloride in 2007. Later, Pspiro chiral tetraaminophosphonium salts with halides as well as carboxylates as counter ions were found to be impressive to induce chirality with high degree of enantioselectivity on alkenes as well as on alkynes. In addition, the performance of binaphthyl based [7.7]-Pspirocyclic arylaminophosphonium barfates was also found to be excellent, especially in photo induced asymmetric catalysis, which is one of the major emerging research areas in the near future. Binaphthyl based phosphonium salts functionalized at 2 and 2’ with phosphonium (2) and hydroxyl, amide, urea and sulphonamide group (2’) respectively, divulged impressive enantioselectivities. Nonetheless, the amino acid based bifunctional or multifunctional asymmetric catalysts obtained after modification in the catalyst backbone with use of amide, urea, and thiourea were found to be excellent, mainly in stereo selective additions and cyclization reactions to form spirocyclic scaffolds. Overall, the hydrogen bonds and electrostatic interaction played a key role in geometry fixation to form the product with a greater enantioselectivity. Future studies will definitely expand the scope of phosphonium salt asymmetric organocatalysis with newer catalyst design and their utility for various organic transformations.

Ph Ar1

Ph O

6. Conclusion

Br P

NH

Bn

O

Bn

O

P

F

165a Yield 92%, ee 50% dr >19:1

NH

N H

Br Ph

P

Ph Ar1

NH

165b Yield 96%, ee 92% dr 11:1 in toluene Yield 98%, ee 94% dr 15:1 in mesitylene as a solvent

Ar1 = 3,5 (CF3)2C6H3

Scheme 43 Effect of catalyst structure on asymmetric addition of γ-malonate-substituted α,β-unsaturated ester 164 to N-benzyl methyleneindolinone 163 a Reaction conditions: 163 (0.06 mmol), 164 (0.09 mmol) and base (0.12 mmol) in the presence of catalyst (5 mol%) in solvent (1.0 mL). bDistereoselectivity determined by 1H NMR analysis of the crude product. R2 CO2R4 O + R3

R1

CO2R4

N Bn

167 R1 = H, 5-Cl/F/I/Br/CH3/OMe, 6-Cl/F/OMe, 7-Cl/F/CH3/Br R2 = CO2Et, CO2Me,COPh

as well as the d.r., whereas, protecting with an acyl group gave worst ee (ee 27%). They also tried to form six-membered spirocyclic ring by reacting 1,1–diethyl 5-methyl (E)-pent-4-ene-1,1,5-tricarboxylate and methyleneindolinone in presence of catalyst 165b, but the catalyst displayed lower yield and ee (yield 60%, ee 38%).

165b Catalyst K2CO3(2 equiv) mesitylene, 0 oC

168

R 4O 2C

CO2R4

R 2O 2C

R3

R1

O N Bn

169

R3 = CO2Me, COCH3, COPh R4 = CO2Me, CO2Et, CO2Bn

Yield 80 to 98% d.r. 5 to 20:1 ee 77 to 99%

Scheme 44 Substrate scope with respect to substituted methyleneindolinone and substituted γ-malonatesubstituted α,β-unsaturated ester

the product yields >90% in all cases with good ee (>80%). Changing the protecting group on nitrogen of oxindolinone moiety from benzyl to methyl caused an increase in ee (91%) slightly, but it lowered the yield

Acknowledgements The authors acknowledge support from DST/NRF South African Research Chair: Fluorine Process Engineering and Separation Technology for postdoctoral funding.

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REVIEW Phosphonium salts in asymmetric catalysis: a journey of a decade’s extensive research work

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Adv. Synth. Catal. Year, Volume, Page – Page Ajij Golandaj*, Akil Ahmad and Deresh Ramjugernath

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