Pentanidium catalyzed enantioselective phase transfer reactions 2

2.1 Introduction to Asymmetric Phase-Transfer Catalyzed Conjugate Addition of Glycinate Schiff base Compounds with active methylene or methine groups could easily undergo asymmetric conj

Chapter 2

Pentanidium Catalyzed Enantioselective Phase-Transfer

Conjugate Addition Reactions

2.1 Introduction to Asymmetric Phase-Transfer Catalyzed Conjugate Addition of Glycinate Schiff base

Compounds with active methylene or methine groups could easily undergo asymmetric conjugate addition with electron-deficient olefins, particularly

αβ-unsaturated carbonyl compounds to afford various functionalized products, which represents an important route for C-C bond formation asymmetric organic synthesis.1 Various functionalized α-alkyl amino acids have been synthesized by enantioselective conjugate addition of glycinate derivatives by chiral phase-transfer catalysis

Corey et al utilized cinchonidinium bromide 11 as a chiral phase-transfer catalyst for

the asymmetric Michael addition of glycinate Schiff base 1 to αβ-unsaturated carbonyl substrates with high enantioselectivities (Scheme 2.1).2 α-Tert-butyl

γ-methyl ester of (S)-glutamic acid, which is highly useful in synthetic applications, could be synthesized by using methyl acrylate as Michael acceptor Besides, when

acrylonitrile was used as an acceptor, product 55c could be easily transformed to diaminoacid 56 (Scheme 2.1).2

O’Donnell 3

et al conducted the Michael addition in a wider scope with the

organic-soluble bases BEMP and BTPP, including acrylate, acrylonitrile, vinyl ketone, and unsaturated sulfone.These representative Michael acceptors were more tolerated

under less basic BEMP condition, excellent yield and ee were achieved (Scheme 2.2).

Scheme 2.1 Highly enantioselective Michael reactions of 1 with catalyst 11

Scheme 2.2 Organic-soluble base BEMP in phase-transfer system

In 2002, Arai et al developed and applied in the asymmetric Michael addition of 1

with acrylate using tartrate-based spiro chiral ammonium salt 57 as phase-transfer

catalyst, only moderate ee and yield was observed (Scheme 2.3).4

Later, Arai’s group synthesized a new binaphthyl-derived bis(ammonium)salt 58 as

an efficient chiral phase-transfer catalyst for the Michael addition reactions (Scheme

2.4) Though only moderate ee was achieved, the most advantage is that the

modification on the ether and ammonium moieties seems quite convenient.5

Scheme 2.3 Tartrate-based spiro chiral ammonium salt 57 as phase-transfer catalyst

Scheme 2.4 Chiral binaphthyl-derived bis(ammonium) salt 58 as phase-transfer

catalyst

Scheme 2.5 Tartrate-derived bis(ammonium) salts 59 as phase-transfer catalysts

Shibasaki and co-workers also invented tartrate-derived, C 2-symmetric

bis(ammonium) salts 59 as phase-transfer catalysts and successfully applied them to the asymmetric Michael addition of 1 to benzyl acrylate (Scheme 2.5).6 Counter-ion

has a significant effect on yield Changing counter ion from iodide (I-) to tetrafluoroborate (BF4-) could dramatically accelerate the reaction and improve the yield

Besides ammonium salt, Akiyama et al developed a chiro-inositol-derived crown

ether 60 as phase-transfer catalyst, which showed good reactivity and selectivity of the asymmetric Michael addition of glycinate Schiff base 1.7 High levels of enantioselectivities were achieved for both alkyl vinyl ketone and acrelate (Scheme 2.6)

Scheme 2.6 Chiro-inositol-derived crown ether as a phase-transfer catalyst

Lygo’s group utilized the quaternary ammonium salt, 61 derived from

(α-naphthylmethyl)-amine, as phase-transfer catalyst to study the reaction parameters

for the asymmetric Michael addition of a glycine diphenylmethyl ester Schiff base 62

to alkyl vinyl ketone 54d, 54i High level of enantioselectivities can be obtained by

conducting reaction in diisopropyl ether at 0 oC in the presence of 50 mol% Cs2CO3

and 1 mol% catalyst (Scheme 2.7).8a Later, Lygo’s group also found that adding mesitol to the reaction could dramatically enhance the reaction rate in the KOH

mediated enantioseletive Michael addition reaction It was revealed that mesitol played

a role of co-catalyst.8b

Scheme 2.7 α-Methylnaphthylamine-derived ammonium salt 61 as phase-transfer

catalyst

Scheme 2.8 Asymmetric 1, 6-addition of 1 to electron-deficien diene with 8 and

formation of optically active pyrrolidine

Jorgensen’s group reported an organocatalytic asymmetric 1, 6-addition of 1 to

electron-deficient α,β-unsubstituted dienes 64a-64d to afford the corresponding

optically active addition products 65-65d in good yields and excellent

enantioselectivities(up to 98% ee), using readily accessible cinchona alkaloid-derived

chiral phase-transfer catalyst 8 The synthetic utility of this asymmetric reaction was

illustrated by the formation of an attractive optically active pyrrolidine 66 from 65b

(Scheme 2.8).9

In the same year, Jorgensen’s group also reported a highly enantioselective conjugate

addition of glycine imine derivatives 67 to electron-deficient allene 6810 Finally, the synthetic value of the chiral products obtained from this reaction was exemplified by

their straightforward transformation to optically active 2, 3-disubstituted γ-lactams 70

(Scheme 2.9)

Scheme 2.9 Enantioselective conjugate addition of 67 to allene 68 and synthesis of

optically active 2, 3-disubstituted γ-lactams

Maruoka’s catalysts (13, 14, 15) showed excellent reactivity towards various

phase-transfer catalyzed reactions In the additive screening experiments, it was found that CsCl played a role of rate enhancement in the phase-transfer catalyzed conjugate

additions of 1 to acrylate (Scheme 2.10). 11a With respect to the enantioselectivity and cost, a combination of K2CO3 and catalytic CsCl is clearly superior to Cs2CO3, which affords the same result as Cs2CO3.

When this strategy (asymmetric conjugate addition with CsCl as additive) is applied to alkyl vinyl ketone, product could be easily transformed to chiral disubstituted

pyrolidine 75 (Scheme 2.11).11b Various functionalized vinyl ketones lead to one-pot

synthesis of hexahydropyrrolizine 78a, and octahydroindolizine core 78b structures

(Scheme 2.12) This approach allows the facile synthesis of a natural alkaloid such as (+)-Monomorine.11b

Scheme 2.10 Enantioselective conjugate addition of 1 with CsCl as additive

Scheme 2.11 Enantioselective conjugate addition with ethyl acrylate and synthesis of 2,

5-disubstituted cis-pyrrolidine 75

Scheme 2.12 Synthesis of hexahydropyrrolizine 78a and octahydroindolizine 78b

Summary

The conjugate addition reactions of glycine ester derivatives with various αβ- unsaturated carbonyl compounds were introduced These reactions provide optical active compounds with high yields and excellent enantioselectivities, which could be

easily transformed to several chiral building blocks, such as chiral γ-lactames,

pyrrolidine, hexahydropyrrolizine and α-amino acid derivatives However, among them, all of the Michael acceptors are electron-deficient terminal alkenes, no

αβ-unsaturated-β-substituted carbonyl compound was reported to realize conjugate addition with glycine ester derivatives So a more general phase-transfer catalyst for both types of acceptors is reasonably required

2.2 Introduction to pentanidium and synthesis of chiral pentanidium

We have developed bicyclic guanidine as chiral Brønsted base catalyst for enantioselective reactions over the past several years.12 As an extension of this work,

we began a program to develop novel structures that are more basic than guanidine

We naively developed structures containing five nitrogen atoms in conjugation, pentanidine, with the hypothesis that this may render it more basic than guanidine Serendipitously, we found that its alkylated salt, pentanidium, turns out to be an

excellent phase-transfer catalyst Herein, we wish to introduce a novel C 2-symmetric chiral pentanidium and its successful application to catalytic enantioselective conjugate addition of tert-butyl glycinate-benzophenone Schiff base to variousαβ-unsaturated acceptors, including vinyl ketones, acrylates and chalcones The IUPAC name for the 5-nitrogen core is diaminomethylidene guanidine and some authors refer to it as biguanide To avoid confusion with guanidine or bis-guanidine,

we describe it as pentanidine (for base) or pentanidium (for salt) Only few

examples of this structure were shown in literatures Early 1966, Bauer synthesized octamethylbiguanide perchlorate as the most highly substituted biguanide (Figure 2.1)

One of the most common methods to introduce fluorine atoms into intermediates is the well-investigated halogen-exchange reaction, in which chloro- and bromo aromatics activated towards nucleophilic substitution, reacting with a fluoride source to yield the corresponding fluoroarenes The use of a new class of very active phase-transfer catalysts gives the possibility of substituting halogens even with weak activation giving

a convenient access to interesting compounds that are not available so far In 2004, Pleschke’s Group developed a new generation of Halex reaction catalyst CNC+(Scheme 2.13, eq 1), which could be easily synthesized by coupling of 2-chloro-1,3- dimethylimidazolinium chloride (DMC) with tetramethyl guanidine (TMG) under basic condition CNC+Cl- performed as an excellent and efficient phase-transfer catalyst for the halogen-exchange reactions (Scheme 2.13 eq 2).14

Scheme 2.13 Halogen-exchange reaction with CNC+ as phase-transfer catalyst Chiral modification of CNC+ is the easiest approach to chiral pentanidium Since diamine was used as the building block of CNC+, chiral diamine could be applied to easily construct chiral CNC+, a chiral pentanidium The structure of various chiral pentanidium salts are shown in Figure 2.2

Figure 2.2 Various chiral pentanidium salts

Representatively, the synthesis of pentanidium chloride 80a requires five steps starting

from commercially available (S,S)-diphenyl-diaminoethane, other commonly available

and inexpensive reagents (Scheme 2.14) Urea 82 was synthesized by treatment of chiral diamine 81 with triphosgene and Et3N, which could be used in the next step

without any purification After methylation with methyl iodide and NaH, 83 was obtained in 80% yield over two steps Then treating 83 with (COCl)2 in reflux condition

in toluene under N2 atmosphere, imidazoline salt 84 was obtained as white solid in full conversion Due to the sensitivity to moisture and air, 84 was treated with ammonia directly without purification and 85 was isolated almost quantitatively The coupling of

84 and 85 under basic condition leads to 80a effectively Chiral pentanidium chloride 80a could be further purified by re-crystallization from CH2Cl2 and ethyl acetate Through the whole protocol, the preparation only requires flash chromatography only once and a single re-crystallization at the end of the synthesis The structure of the

chiral pentanidium salt was confirmed by single-crystal X-ray diffraction analysis

(Figure 2.3)

Scheme 2.14 Synthesis protocol of chiral pentanidium chloride 80a

Figure 2.3 Single-crystal X-ray diffraction analysis of 80a

Particularly, the following steps are required for the synthesis of 80b, since the direct transformation from 86 to 88 with (COCl)2 is not successful (Scheme 2.15).15 Chiral

pentanidium salts 80f and 80g are colorless oil, thus instead of re-crystallization, flash

chromatography was required for the last purification step (CH2Cl2/MeOH, 50:1)

Scheme 2.15 Transformation from 86 to 88 by using lawesson’s reagent

Chiral pentanidium salts 80d and 80e were obtained by ion-exchange with

corresponding sodium salt Details were included in experimental chapter

Conjugate Addition Reactions

2.3.1 Optimization of Michael addition of glycine Schiff base 1 with ethyl vinyl ketone

Michael addition of tert-butyl glycinate-benzophenone Schiff base 1 has been

previously evaluated by several groups under either phase-transfer conditions or homogeneous conditions.2-8 As a preliminary study, phase-transfer catalytic Michael

addition between Schiff base 1 and ethyl vinyl ketone 54b was conducted by using pentanidium 80a

With 2 mol% of the catalyst (S,S)-80a and 50% aq KOH as base, the reaction was completed in 5 minutes at room temperature, affording adduct 55b with 45% ee

According to Jørgensen and Maruoka’s pioneer works, 9, 10, 11 base is one of the key factors that affect the enantioselectivities dramatically So the priority of optimization was determined to be base screen

After screening various bases, it was found that strong bases accelerated reaction rate too fast and weak bases have no activity (Table 2.1, entries 3, 4, 10 and 6, 8) Only

Cs2CO3 and CsF provided considerable ee, 65% and 71% respectively (Table 1, entry 7

and 12) Since reaction rate catalyzed by Cs2CO3 is much faster than CsF (30 min vs 12h), Cs2CO3 was chosen to continue the further optimization,

Table 2.1 Base screening for Michael addition reactions of Schiff base 1 with ethyl

vinyl ketone 54b

entrya base time conversion(%)b ee(%) c

Reactions were performed by using 1 (0.02 mmol), and 54b (0.04 mmol) in 0.2 mL toluene for indicated

time b Conversion was determined by TLC c Determined by HPLC analysis using Chiralcel OD-H column d Though CsF provides higher ee, the reaction rate is quite lower than Cs2CO3, and there’s no reaction at 0 oC for 24 h using CsF

even though CsF afforded slightly higher ee Base’s amount has notable effect on the

reaction rate, and no remarkable effect on the enantioselectivity The reaction rate is slow in the presence of 1.0 equiv base and too much base is also not necessary (10.0 equiv base) So, optimal amount of base was determined to be 5.0 equiv After decreasing reaction temperature to 0 oC, ee increased dramatically to 83% In the aspect

of catalyst

Table 2.2 Solvent screen for Michael addition reactions of Schiff base 1 with 54b

entrya solvent time conversion(%)b ee(%) c

a Reactions were performed by using 1 (0.02 mmol), and 54b (0.04 mmol) in 0.2 ml solvent for indicated

time b Conversion was determined by TLC c Determined by HPLC analysis using Chiralcel OD-H column

loading, higher catalyst loading (5 mol%, 10 mol%) did not provide better enantionselectivities and lower catalyst loading (0.1 mol%, 0.5 mol%) afforded lower reactivity and longer reaction time 2 mol% was determined to be optimal for this

reaction Next stage was solvent and catalyst screen

Several common solvents were screened Only diethylether afforded comparable ee

value with toluene (Table 2.2, entry 7) Reactions in other solvents finished in 1h~10h, except CHCl3 (entry 5) Unfortunately, no better result was observed Notably, reaction proceeded in CH2Cl2 led to almost racemic product (entry 2) Generally, chlorinated solvent is not suitable for pentanidium catalyzed phase-transfer reaction, which differs from previous catalysts To some extent, reaction avoiding chlorinated solvent would be more environmentally friendly

Having defined the optimal solvent and base, various pantanidium salts 80a-80g were tested Ethyl substituted pentanidium 80b shows slightly lower selectivity comparing with 80a (Table 2.3, entry 2), while 80c with modification at aromatic groups,

provides same level ee with 80a (entry 3) Counter ion has significant effect on enantioselectivity Tetrafluoroborate pentanidium 80d gives 80% ee, while 80e only provides 57% ee (entry 4,5) Pentanidium 80f, derived from (S, S)-cyclohexane-1,

2-diamine, leads to almost racemic product (entry 6) When non-C 2 symmetric

pentanidium 80g was employed, low enantioselectivity was observed, 37% ee (entry

7)

Table 2.3 Catalyst screen for Michael addition reactions of Schiff base 1 with 54b

entrya catalyst temp/oC solvent yield (%)b ee (%) c

a Reactions were performed by using 1 (0.02 mmol), and 54b (0.04 mmol) in 0.2 mL toluene for 2

hours b Yield of isolated product c Determined by HPLC analysis using Chiralcel OD-H column

At the same time, the ratio and concentration effect were also investigated by tuning the solvent’s amount Unfortunately, no significant improvement was observed The

best ratio and concentration was determined to be: 1 : 54b = 1:2; c = 0.1 M

Finally, several benzene-derived solvents were screened, such as ethyl benzene, m-xylene, p-xylene, mesitylene Delightedly, mesitylene was found to afford the

highest ee among them, up to 89% When the reaction temperature was further

decreased to -20 oC, ee value improved to 93%

Table 2.4 Ratio and concentration effect on Michael addition reactions of Schiff base

2.3.2 Substrate scope of Michael addition of glycine Schiff base 1 with 54

With the optimal reaction conditions established, we studied the phase transfer

conjugate addition of 1 with various vinyl ketones and acrylates (Table 2.5) Both alkyl

vinyl ketones 54b, 54d, 54j and phenyl vinyl ketone 54k gave excellent ee values

(entries 1-4) Low yield of adduct 54k (entry 4) might be due to double additions.8b Acrylates 54g, 54h also provided good yields and excellent enantioselectivities