Acylation Reactions Catalyzed by

REVIEW

971

Transesterification/Acylation Reactions Catalyzed by Molecular Catalysts Transeterifcation/AcylationReactionsCat lyzedbyMolecularCat lyst A. Grasa,a Rohit Singh,b Steven P. Nolan*b Gabriela a

Johnson Matthey Catalysts Chiral Technologies, 28 Cambridge Science Park, Milton Road, CB4 1FP, Cambridge, UK Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA Fax +1(504)2806445; E-mail: [email protected] Received 20 January 2004; revised 16 February 2004 b

Abstract: A survey of catalysts able to mediate the transesterification/acylation reaction is presented. Metal and organic catalysts are capable of facilitating this important transformation. 1 2 2.1 2.2 2.3 2.4 3 3.1 3.2 4

Introduction Transesterification Reactions Catalyzed by Lewis Acids Lanthanide (Sm) Catalysis Tin Catalysis Indium Catalysis Yttrium Catalysis Transesterification Reactions Catalyzed by Nucleophilic Catalysts Superbase-Catalyzed Transesterification of Esters with Alcohols Nucleophilic N-Heterocyclic Carbene (NHC) Catalysis Conclusions

Key words: transesterifications, acylations, catalysis, carbenes, esters

1

Introduction

The ester/acyl moiety represents one of the most ubiquitous functional groups in chemistry, playing a paramount role in biology and serving both as key intermediate and/ or protecting group in organic transformations. In addition to its importance in organic syntheses, the ester unit has found important industrial applications as a building block for transformations such as polymerization (ring opening of lactones), polycondensation, or macrolactonization reactions. Esters are usually synthesized from carboxylic acids and alcohols. However, this reaction suffers from harsh reaction conditions. As a consequence, efficient methods for the synthesis of esters are potentially very useful. An alternative route to ester synthesis is acyl transfer from an acylating agent such as an acyl chloride, acid anhydride, or an ester. Lewis acidic catalysts such as Sc(OTf)3 and Sc(NTf2)3,1 TiCl(OTf)3,2 TMSCl and TMSOTf,3 La(Oi-Pr)3,4 COCl2,5 Sn(OTf)2,6 and TiCl4/ AgClO4,7 or nucleophilic catalysts such as phosphines8 have been used as catalysts or stoichiometric reagents to mediate the reaction between an ester and an acyl chloride or an acid anhydride (Scheme 1, equation 2 and 3). In this context, the base or Lewis acid-catalyzed acylation of alcohols by acetic anhydride or acid halides suffers from poor selectivity between primary and secondary alcohols SYNTHESIS 2004, No. 7, pp 0971–0985xx. 204 Advanced online publication: 14.04.2004 DOI: 10.1055/s-2004-822323; Art ID: E10504SS © Georg Thieme Verlag Stuttgart · New York

or cleavage of acid-sensitive functional groups. On the other hand, tertiary phosphines suffer from poor air-stability, toxicity, and flammability. Transesterification (Scheme 1, equation 4) represents a mild and versatile alternative to esterification reactions between an acid and an alcohol (Scheme 1, equation 1). This transformation takes place via an alkoxy moiety exchange between an ester and an alcohol. The transesterification of an ester by exchange of an alkoxy moiety has been efficiently achieved using enol esters as acylating agents. Conversion of the resulting enolate to an aldehyde or ketone subsequently shifts the transesterification equilibrium in the desired direction. Due to its simplicity and versatility, and as a consequence frequent use, of the transesterification reaction in organic synthesis, the exchange between esters and alcohols, catalyzed by acids, bases, or enzymes has generated numerous studies and several comprehensive reviews have been published on this subject.9 Specifically designed catalysts have been shown to play a key role in optimizing the efficiency of a wide variety of organic transformations. During the past few decades, small molecule synthesis has attracted attention owing to its importance in the preparation of key intermediates and compounds in pharmaceutical, agrochemical, and fine chemical industries. To this end, we propose to review recent advances in transesterification/acylation reaction protocols involving alcohols and esters catalyzed by molecular catalysts. O R

+ R''OH OH (1)

O R

O O

+ R''OH

O

(2) R

R

(3) O R

Scheme 1

OCl

O

(4) OR''

+ R''OH

R

OR'

+ R''OH

972

REVIEW

G. A. Grasa et al.

2

Transesterification Reactions Catalyzed by Lewis Acids

2.1

Lanthanide (Sm) Catalysis

Samarium complexes are widely used in organic synthesis and recently several catalytic applications of samarium(II) such as hydroboration,10 hydroamination11 and hydrogenation12 of alkenes, Diels–Alder, aldol,13 or intramolecular Tishenko14 reactions have been reported. In light of the activity of Sm(II) compounds, especially that of the Cp*2Sm(thf)2 complex, towards enol esters in the 1:2 cross-coupling reaction of vinyl esters with aldehydes,15 Ishii et al. used this catalyst successfully in the transesterification reaction (Table 1).16 This catalyst is most suitable for acylation of alcohols using enol esters as acylating agents (Table 1, entries 1 and 2) since the enolate is converted to the corresponding aldehyde or ketone. On the other hand, since transesterification is an equilibrium process, excess of one of the reactants helps improve the outcome of the reaction (Table 1, entries 1 and 2). While ethyl acetate leads to moderate conversion to the corresponding ester, acetic anhydride or acetic acid lead

to decomposition of the catalyst and hence very low conversions (Table 1,entries 3-5). Other samarium catalysts have been tested and compared with the Lewis acid, Al(Oi-Pr)3, which is an active catalyst for acylation of alcohols with acetic anhydride. However, this aluminum Lewis acid gives unsatisfactory results when vinyl acetate is employed as acylating agent. Sm(III) compounds [SmI3, Sm(OTf)3and Sm(Oi-Pr)3] also behave as transesterification catalysts, although they affect this transformation to a smaller extent. The authors concluded that the active species involved in the catalytic cycle might be a Sm(III) species resulting from coordination of the enol ester to the Cp*2Sm(thf)2 complex. An activity study of Cp*2Sm(thf)2 in the transesterification of various alcohols with enol esters shows this complex acts as a very efficient catalyst for the reaction of primary alcohols with enol esters under mild reaction conditions and in relatively short reaction times (Table 2, entries 1–14), while SmI2 leads to lower conversions under similar conditions. Also, unsaturated esters undergo transesterification with primary alcohols, which represents an advantage since unsaturated carboxylic acid derivatives

Biographical Sketches

Synthesis 2004, No. 7, 971–985

Gabriela Grasa was born in 1972 in Romania. She received her BSc and MSc in chemistry from The University of Bucharest. She received her PhD in chemistry from the University of New Orleans in December 2002

under the supervision of Dr. S. P. Nolan. Her main research interest during her PhD was the development of catalytic systems bearing N-heterocyclic carbenes as ligands. She joined Johnson Matthey Catalysts, Chiral

Technologies in January 2003 as a Senior Research Chemist and her current research is focused on metalcatalyzed asymmetric hydrogenation.

Rohit Singh was born in 1977 in Dibai, India. He studied chemistry at Panjab University, Chandigarh in India and received his MSc (Hons) in 2001. He joined

the University of New Orleans as a PhD student in 2002 and subsequently joined Dr. S. P. Nolan’s research group. His current research interests are focused

on the development of Nheterocyclic carbenes as efficient catalysts for organic reactions.

Steven P. Nolan was born in Quebec City, PQ, Canada in 1962. He received his BSc in chemistry from the University of West Florida and his PhD from the University of Miami where he

worked with Professor Carl D. Hoff. After a postdoctoral stay with Professor Tobin J. Marks at Northwestern University, he joined the Department of Chemistry of the University of New Or-

leans in 1990. He is now University Research Professor of Chemistry. His research interests include organometallic chemistry and homogeneous catalysis.

© Thieme Stuttgart · New York

REVIEW

Table 1 Influence of the Acylating Agent and of the Catalyst on the Acylation of 1-Octanol O O

Entry 1

973

Transesterification/Acylation Reactions Catalyzed by Molecular Catalysts

+

C8H17OH

Cp*2Sm(thf)2 (0.1 mmol)

O

Acylating Agent

Alcohol

Vinyl Ester

Yield (%)a,b

1

Yield (%)a,b

O

C8H17OH

>99 O

O

Cp*2Sm(thf)2

Entry OC8H17

r.t. , 3 h

Catalyst

Table 2 Cp*2Sm(thf)2-Catalyzed Acylation of Various Alcohols with Enol Esters

86c

2

C8H17OH

>99

3

C8H17OH

O

4

C8H17OH

O

O

O

2

Cp*2Sm(thf)2

O

99

O

>99

O

3

Cp*2Sm(thf)2

O

66

O

>99

O

4

Cp*2Sm(thf)2

O

5

Cp*2Sm(thf)2

O

O

40

O

5

O

SmI2 SmI3

C8H17OH

9

C8H17OH

10

PhCH2OH

10

Al(Oi-Pr)

30

O

>99

O Ph

O

>99

O O

13

O

>99

O

99

O

Sm(OTf)3

8

>99

O

O

9

C8H17OH

54

O

Sm(Oi-Pr)

7

O O O

O

8

C8H17OH

18

O O

7

6

>99

O Cl

OH

6

C8H17OH

NR

O

96

O O

O

11

>99

CH2OH

a

Reaction conditions: catalyst (0.1 mmol), toluene (1mL), 1-octanol (1 mmol), acylating agent (2 mmol). b GLC yields. c Vinyl acetate (1 mmol).

O O

12

OH

88

O O

13

O

OH

>99

O O

are not readily available. Acylation of secondary alcohols is carried out with isopropenyl acetate as the reagent of choice. Of note are acylations of tertiary alcohols with vinyl acetate mediated by Cp*2Sm(thf)2 which are sluggish.15

14

2-Octanol

O

15

2-Octanol

O

O

OH

O

As mentioned above, the transesterification reaction is a more difficult process due to its reversibility, however it can benefit from the use of the more reactive enol esters, since the resulting alcohol is irreversibly converted to the corresponding aldehyde or ketone.

17

Cl Bu O

Sn

Cl

Cl

Sn

O

Sn

Bu

Bu Cl 1

Figure 1

Bu

Sn

O

OH

18

19

11

O O

OH

51

O O

Bu Bu

>99

O

OH

Bu

>99

O

Tin Catalysis

Bu

95 O

16

2.2

54

a

Alcohol (1 mmol), vinyl ester (2 mmol), of Cp*2Sm(thf)2 (10 mol%), toluene (1 mL), r.t., 3 h. b The yield is based on the alcohol.

Synthesis 2004, No. 7, 971–985


974

REVIEW

G. A. Grasa et al.

Distannoxane 117 has been used in catalytic amounts to promote the transesterification of enol esters with primary alcohols (Table 3).18 This process takes place under mild, virtually neutral conditions, which makes this specific process advantageous when Lewis acid sensitive substrates are employed (Table 3, entry 9). Alkenyl esters behave as efficient acylating agents mainly for primary alcohols. In some instances, secondary alcohols require higher reaction temperature and higher catalyst loading, while phenol and cyclohexanol do not react under these reaction conditions. Importantly, acid sensitive functional groups are inert to this catalyst and therefore the transesterification reaction proceeds smoothly, unlike the Sc(OTf)3-catalyzed transesterification. The fact that this method is not efficient for the acylation of secondary alcohols has important repercussions in synthesis, since a primary alcohol can be selectively acyl-protected in the presence of a secondary alcohol.

Table 3 Transesterification of Enol Esters with Alcohols Catalyzed by Distannoxane 1 Entry

Vinyl Ester

1

C8H17OH

2

C8H17OH

3

C8H17OH

4

C8H17OH

5

C8H17OH

Yield (%)a,b 99

O O

96

O O

98c

O Ph

O

99c

O O

97c

O O

6

C8H17OH

96c

O Cl

Indeed, this catalyst discriminates between primary and secondary alcohols or phenols, selectivity not attainable using catalysts such as alkoxides.

2.3

Alcohol

O

7

PhCH2OH

O

8

PhCH2OH

O

9

TBSO(CH2)4OH

O

CF3CO2(CH2)4OH

O

98 O

Indium Catalysis

98 O

Indium halides have been successfully employed in various organic transformations,19 including transesterification.20 The catalyst can be generated in situ with the corresponding alcohol prior to ester addition. A variety of alcohols, especially tertiary alcohols, which are less active substrates, undergo acylation with carboxylic esters. However, InI3 is not sufficiently catalytically active and complete conversions to product are obtained only when the complex is employed as a stoichiometric reagent. On the other hand, unlike most transesterification catalysts, InI3 presents the advantage of favoring the transesterification of esters bearing tertiary alcohol moieties over primary alcohol moieties. (Table 4).

98 O

10

97 O

11

NR

O OH O

12

OH

O

C6H13

13

11

O

OH

97d

O

C6H13

O

14

NR

O OH O

2.4

a

Isolated yields. Catalyst: 1–10 mol% . c 50 °C. d Reflux.

Yttrium Catalysis

b

N(SiHMe2)2 tBu

N O Y OiPr

Y5(O)(OiPr)13

tBu

Y

O

N tBu

O

O t

tBu

Bu thf

tBu

2

(2) [Y(thd)2(OiPr)]

(3)

(4) LY[N(SiHMe2)2](thf)

Figure 2

Well defined yttrium complexes bearing b-ketonates 221 or salen 422 as ligands, or yttrium pentameric aggregates 323 have been successfully employed as transesterification catalysts achieving high turnover numbers.24,25 Although primary alcohols can be acylated using both vinyl or isopropenyl acetate with high turnover frequencies, Synthesis 2004, No. 7, 971–985


for the acylation of secondary alcohols, isopropenyl acetate is the reagent of choice (Table 5).24 Moreover, the Lewis acidity of this catalyst does not interfere with functionalities such as double bonds (Table 5, entry 5) or epoxides (Scheme 2). This yttrium alkoxide catalyst presents the advantage of selectively acylating primary alcohols over secondary. When poly-secondary alcohols are employed, the equatorial hydroxyl group is acylated exclusively (Scheme 3). Remarkably, although it is known that enol esters react with amines in the absence of catalysts,26 the use of 2-amino-2-deoxy-4,6-di-O-phenyl-methyl-a-D-glucopyranoside leads to the selective formation of the O-acylated product (Scheme 4).

REVIEW Table 4


InI3-Catalyzed Transesterification of Esters with Alcohols

Entry

Alcohol

1

MeOH

Table 5 Acylation of Various Alcohols with Isopropenyl Acetate Catalyzed by Yttrium Complexes

Yield (%)a

Ester

Entry

5

MeOH

HO

3

OMe

89

OH

OEt

4

HO

5

Ph

OH

>99

3 (200)

>99

3 (50)

NRb

2 (50)

98b

2 (50)

84b

2 (50)

NRb

OH

OMe

7

68

O Ph

a

6

70

O

t-BuOH

3 (100)

OH

OMe

9

>95

90

O

Ph

3 (217)

OMe

MeOH

t-BuOH

>99

OCH2Ph O

Ph

8

3 (118)

88

O Ph

7

>99

89

O

PhCH2OH

3 (200)

OiPr

Ph

6

OH

2

85

O Ph

i-PrOH

Yield (%)a

OMe

MeOH

4

Catalyst (S/C)

90

O Ph

3

1

OiPr

i-PrOH

Alcohol

86

O Ph

2

975

OH

OMe

Isolated yields.

8

Having demonstrated that yttrium alkoxides efficiently catalyze the acylation of secondary alcohols,24 RajanBabu and Lin examined the synthesis of chiral Y-salen complexes and their activity in the kinetic resolution of secondary alcohols.27 Y-Salen complex 4 catalyzes the acylation of secondary alcohols in a very short reaction time and at low temperature (Table 6). The kinetic selectivity varies as a function of the alcohol used, when 2-indanol was used the highest enantiomeric excesses and highest activities were achieved (Table 7).

HO

9 OH a b

Neat isopropenyl acetate. Stoichiometric amount of enol ester.

3

Transesterification Reactions Catalyzed by Nucleophilic Catalysis

Due to the high demand for efficient and versatile methods for the synthesis of fine chemicals and pharmaceutiO

H

O OH

O

0.5 mol% 3 r.t., 5 min

+ O

H OAc

> 95%

Scheme 2 OH

O

OH

OtBu

OtBu

O

3 mol % 3

+ O HO H

OH

O

r.t., 24 h AcO

OH

H 93%

Scheme 3

Synthesis 2004, No. 7, 971–985


976 Table 6 Entry

REVIEW

G. A. Grasa et al. Y-Catalyzed Acylation of Secondary Alcohols

Table 7

Kinetic Resolution of Secondary Alcohols Catalyzed by 4 Alcohol

Alcohol

Catalyst (mol%)

T (°C)

Yield (%)

Entry

HO

3 (5)

–3

63

1

2

4 (1)

–3

65

3

3 (1) + salen (5 equiv)

–20

100

4

4 (1)

22

100

3 (5)

–27

35

1

5

OH

OH

2

OH

3

OH

4 6


22

97

7

4 (1)

22

51

3 (5)

–27

38

8

OH

OH

5

OH

Catalyst 4 (mol%)

T (°C)

Yield (%)

ee (%)

1

–3

65

23 (S)

2

–10

39

14 (R)

1

–25

76

91 (R)

1

–3

61

36 (S)

2

–10

42

13 (S)

Ph

9 10


–25

77

4 (1)

–22

95

H Ph

3.1

H

O O HO

O

3 mol% 3 r.t., 2 h

+ O

Ph

Commercially available non-ionic superbases such as proazaphosphatranes 5 and 6,33 developed by Verkade, are known to deprotonate activated methylene groups34 and to catalyze several processes such as the trimerization of isocyanates35 or the protective silylation of alcohols.36 Compound 5 is also a powerful catalyst for the transesterification reaction of methyl esters with alcohols.37

O O AcO

H2N

H2N

OBn

OBn

82%

Scheme 4

cals, there has been a growing interest in finding metalfree catalyzed processes that would provide efficient alternatives to classical organic transformations and result in more economical and environmentally friendly chemistry. A few notable examples include the enantioselective pyrrole-catalyzed 1,3-dipolar additions,28 and the prolinecatalyzed Mannich reaction for the enantioselective synthesis of a- or b-amino acids and b-lactams.29 Chiral dimethylamino pyridine derivatives also have been efficiently employed as nucleophilic catalysts for the dynamic kinetic resolution of secondary alcohols using acetic anhydride as the acylating reagent30,31 and nonenzymatic resolution of amines.32 H3C

P N

N CH3 N

H3C

CH3

CH3 H3C

P N

Both primary and secondary alcohols are activated by this catalyst in the transesterification reaction involving either methyl esters (Table 8) or enol esters as substrates (Table 9). However, this catalyst is extremely reactive and in some instances displays poor functional group tolerance and poor selectivity. For these reasons, Verkade et al. turned their attention to less basic derivatives such as iminophosphoranes 7 and 8.38 Indeed, with catalyst 8 both primary and secondary alcohols show high activities in the transesterification of primary alcohols with enol esters (Table 8) and high selectivity with respect to primary alcohols when both primary and secondary alcohols are used.39 Various functional groups (e.g. TBS, disulfide, epPh

CH3 CH3 CH3

N P

H3C N

CH3 N CH 3 N

H3C Ph N

N P

CH3

H3C N CH3

N

N 5

6

Figure 3

Synthesis 2004, No. 7, 971–985

N N

Superbase-Catalyzed Transesterification of Esters with Alcohols


N 7

8

CH3 N CH3

REVIEW Table 8

Transesterification of Esters with Alcohols Catalyzed by 5

Entry

Alcohol

1

EtOH

Table 9 Acylation of Alcohols with Enol Esters Catalyzed by Catalysts 5–8

Yield (%)a

Ester

Entry Alcohol

3

1

O

OH

2

91

OH

O Ph

4

OH

85

5

OH

NR

6

OH HN Boc O

7

OH

3

O

H N

5

99

5

99

4

O

7

99

5

O

8

99

8

94

8

87

6

91

5

97

5

NR

5

98

8

99

5

98

8

99

8

99

8

98

8

74

O

96 O

b

6

O Ph

CH3

7

O O

Ph

95

O O

O

8

OH

O

Ph

CO2Me

O

9

OH

O

a

Catalyst 5 (10 mol%). b Catalyst 6 was used.

O

10

oxide, and acetal) tolerate catalyst 8 under the reaction conditions. Recyclable transesterification catalysts can be obtained by grafting iminophosphoranes 7 and 8 onto polymeric supports (Scheme 5), therefore making the use of such a ‘green’ catalyst, very attractive.

O OH

Nucleophilic N-Heterocyclic Carbene (NHC) Catalysis

NHCs represent a class of ligands with a considerable stabilizing effect in organometallic systems40 compared to the widely utilized tertiary phosphines. In terms of reactivity, NHCs behave as nucleophiles.41 NHCs have been shown to efficiently promote organic transformations such as the benzoin condensation,42 and ring-opening polymerization of lactones and lactides.43 We have reported that the NHC/IMes catalyzes the reaction of benzyl alcohol with vinyl acetate in THF, with almost quantitative conversion to benzyl acetate in 5 minutes at room temperature (Scheme 6).44a Hedrick simultaneously reported a closely related protocol for NHC-catalyzed transesterification/polycondensation reactions.44b Transesterification reactions of enol acetates with alcohols (such as geraniol and cinnamyl alcohol and alcohols bearing acid-sensitive functional groups) proceed rapidly in the presence of 1 mol% of IMes giving quantitative yields of the desired products (Table 10). Acrylic esters

O

11

O

OH

O

12

OH

13

3.2

99

O

CH3

O

CO2Me

5

O

96

O

Yield (%)a

O O

Ph

OH HN Boc O

8

H N

Catalyst (mol%)

O

82

OH Ph

Enol Ester

89

O OMe

2

977


O OH

14

O OH

15

O OH

O

16

S

HO

17

OH

S

N OH O

NO2

can be problematic substrates for transesterification due to side reactions such as isomerization and/or polymerization. Vinyl acrylate effectively protected benzyl alcohol, albeit requiring a higher loading of the more active catalyst ICy (entry 8).44a,45

Synthesis 2004, No. 7, 971–985


978

REVIEW

G. A. Grasa et al.

H 3C

N P

H3C

N3

CH3

N

H3C N CH3

CH3 N CH3

N P

CH3

H3C N

benzene, reflux

CH3

CH3 N CH3

8b

H 3C N

CH3 N CH 3 N

P

N3

N P

H3C N

CH3 N CH 3 N

benzene, reflux N N 7a

5

Scheme 5

Polymer-supported iminophosphoranes

N N O +

O

HO

O

0.5 % IMes THF, r.t., 5 min

O + O

Ph

H

97%

Scheme 6

IMes-catalyzed acylation of benzyl alcohol with vinyl acetate

As previously mentioned, selectivity in protecting a primary alcohol in the presence of a secondary alcohol is sometimes crucial in natural product synthesis. Transesterification selectivity using IMes as catalyst shows that benzyl alcohol is almost exclusively acylated by vinyl acetate in the presence of 2-butanol (Scheme 7).45 Esterification of 1,2-hexanediol with vinyl benzoate also showed the same activity. Almost exclusive formation of the monoacylated product was observed under similar conditions.46 These NHC catalysts also affect the acylation of the commercially available and more challenging substrate, meth-

N O

HO O

+

+

2 equiv

HO

yl acetate. Two main factors were identified for biasing the reaction in the desired direction. First, the use of 4 Å molecular sieves to absorb the liberated methanol led to quantitative conversion of benzyl alcohol to benzyl acetate. Second, the nature of the nucleophile also influenced the transesterification equilibrium. The more nucleophilic alkyl-substituted ICy, It-Bu, and IAd performed much better in the model reaction affording the product quantitatively.44a,45 Strongly nucleophilic amines, such as DMAP,47 DABCO,48 and DBU,49 known to catalyze the acylation of alcohols with acyl chlorides or acid anhydrides, are not effective catalysts for the transesterification of methyl acetate with benzyl alcohol (Scheme 8).

N O

O

0.5 % IMes

O

THF, r.t., 5 min

1 equiv

Ph

+

O

:

9

1

O N

O

N

OH O

+

Ph

Ph

Synthesis 2004, No. 7, 971–985


O

O O

1 equiv

IMes-catalyzed selective acylation of primary alcohols

O

+

O

9

Scheme 7

Ph

0.5 % IMes

HO

THF, r.t., 15 min 2 equiv

OH

:

1

REVIEW Table 10 O


Acylation of Primary Alcohols Using Enol Esters IMes

R'' +

R'

Entry 1

O

O +

ROH THF, r.t.

O

Ester

R'

OR

Alcohol

R''

Product

IMes (mol%)

O OH

O

2

979

O

Time (min)

Yield (%)a

1

60

99

1

15

96

0.5

15

100

0.5

5

93

2

60

93b

1

30

95b

1

180

95b

OAc

OH

OAc

O

3

O

O

O O

4

OH

O O

O

OH O

5

O

O

6

O

OH

O

Ph

O

OH O

O

O

Ph

O O

7

OAc

O

OH

OAc

Ph

O a b

Reaction conditions: benzyl alcohol (1 mmol), enol ester (1.1 mmol), IMes (0.5–2 mol%), r.t., isolated yield. Enol ester (2 mmol).

The NHC-catalyzed transesterification of widely available methyl or ethyl esters (not commonly used as acylating agents due to their inertness to transesterification) with both primary and secondary alcohols proceeds smoothly, at room temperature and low catalyst loadings leading to high conversions (Table 11). This method can be important since the resulting benzyl or allyl esters can be cleaved under much milder conditions than the corresponding methyl esters.50 While selectivity of NHC-catalyzed acylation of alcohols with respect to primary alcohols can be directed using enol esters,44a reactivity with respect to secondary alcohols44b can be manipulated using methyl esters and higher catalyst loadings (Table 11). This is of interest since the acylation of secondary alcohols might prove an attractive alternative to enzymatic transesterification of racemates.45 The scope of this reaction has been expanded by acylation/transesterification of secondary alcohols possessing various electronic and steric properties (Table 12).46 Different aliphatic and benzylic secondary alcohols were found to be tolerant to the NHC-catalyzed transesterification with methyl acetate. The presence of different functionalities such as alkene, cyclopropyl ring, or two aryl substituents was found to be fully compatible with the

methodology (Table 12, entries 2, 7, and 8). Variation of the para-aryl substituent did not show any significant (or deleterious) electronic effect on the reaction times or yields (Table 12, entries 4, 5, and 6). A limited study focusing on steric effects illustrated that increasing the steric bulk at the a-position to the hydroxy group greatly hinders the reaction rates (Table 13). Using ethyl acetate as the acylating agent, all reactions followed the same trends as with methyl acetate but led to slightly lower yields presumably owing to poorer leaving group capabilities of the ethoxy group as compared to the methoxy functionality. Since transesterification/acylation is an equilibrium process, judicious choice of alcohol/ester combination can direct the formation of the target ester. The formation of methyl acetate is thermodynamically favored and therefore methyl alcohol will easily replace/ exchange the alkoxy moiety of the reactant ester,51 while more highly substituted alkyl alcohol homologues have a lower reactivity with respect to the acylation reaction. The most commonly used method to shift the equilibrium to obtain the desired ester is to remove the resulting alcohol either using partial vacuum or by azeotropic distillation, both methods can prove difficult when low boiling point esters or alcohols are targeted. The transesterification equilibrium can be perturbed in the desired direction (Scheme 9) by replacing ethanol from ethyl acetate by its Synthesis 2004, No. 7, 971–985


980

REVIEW

G. A. Grasa et al. O

Catalyst (2.5 mol%)

+ HO OMe

4 Å M. S., r.t., 1 h

N

N

O O

N

N

N

ItBu 100%

ICy 100%

N

N

N

IPr 45%

N

N

N

SIPr 21%

N

N N

N

DMAP 15%

N

DABCO 45%

DBU 24%

Reaction of methyl acetate with benzyl alcohol catalyzed by various nucleophiles

lower homologue methanol. On the other hand, the use of 4 Å molecular sieves to absorb the generated methanol drives the reaction towards the formation of the higher ester homologue. Imidazol-2-ylidene carbenes are considerably less stable to air and moisture than their corresponding imidazolium salts. Although NHC bearing less bulky alkyl substituents on the nitrogen atoms are more active for the transesterification reaction of less active esters, they are more difficult to isolate since they can easily dimerize. These catalysts can be generated in situ from the corresponding imidazolium salts, avoiding the separation step and handling of the NHC. Both Nolan45,46 and Hedrick44b have reported using this method for generating the carbene catalyst in situ either for the transesterification of esters with alcohols or for the ring opening polymerization of cyclic aliphatic esters. Using a similar procedure, catalytic amounts of imidazolium salt and base stirred at room temperature for 15 minutes in THF, followed by substrate addition leads to comparable activity/yields as when isolated NHCs were used (Schemes 10 and 11).45,46

+ H3C

An additional application of these nucleophilic catalysts is in the synthesis of drug intermediates such a haloalkyl

OCH3

O

CH3CH2OH

+ 96 %, No M. S., 15 min, r.t.

Influence of the use of molecular sieves on the equilibrium

Synthesis 2004, No. 7, 971–985

Notably, commercially available alkyl-substituted ionic liquid IEtMe·HBF4 (1-ethyl-3-methylimidazolium tetrafluoroborate) was used both as ionic liquid and catalyst precursor for the synthesis of polyaliphatic esters of controlled molecular weight, by Hedrick et al.43b The carbene catalyst can be generated in situ in the presence of t-BuOK in THF and at the same time extracted in THF (immiscible with the ionic liquid) in order to perform ring opening living polymerization of cyclic esters. This process is both synthetically and economically attractive since the carbene catalyst affords high molecular weight polylactides with relatively narrow polydispersities and it can be recycled/recovered at the end of the reaction by adding [R3NH]BF4. In subsequent studies, NHCs have been shown to catalyze the transesterification of diesters with diols. One particular striking example is the self-condensation of BHET [bis(2-hydroxyethyl)terephthalate] to generate poly(ethyleneterephthalate) (PET) with properties identical to commercial PET (Scheme 12).44b

91 %, 4 Å M. S., 60 min, r.t.

O

Scheme 9

N

N

SIMes 21%

Scheme 8

N

IAd 100%

IMes 93%

N

Ph


H3C

OCH2CH3

CH3OH

REVIEW Table 11

Entry


981

Transesterification of Methyl Esters with Various Alcoholsa

Ester

1

O

2

O

Alcohol OH

ICy (mol%)

Time (min)

Yield (%)

2.5

60

95a

2.5

30

90a

3.5

60

92a

3.5

60

96a

2.5

30

95b

5

120

89b

2.5

180

97b

2.5

30

99b

2.5

15

96b

5

120

88b

2.5

30

93c

OMe O OMe

3

O

4

O

OH

O OH

OMe

OH

OMe

5

O MeO

OH OMe

OMe

6

O MeO

OMe

OH

O

OH

OMe

7

OMe

8

O O

9

OMe

O

OH

OH OMe

O2N

10

O OMe

OH

O2N

11

O MeO

OH OMe

a

Reaction conditions: alcohol (1 mmol), methyl acetate (1 mL), 4 Å molecular sieves (0.5 g), r.t. Reaction conditions: alcohol (1.5 mmol), methyl ester (1mmol), THF (1mL), of 4 Å molecular sieves (0.5 g). c Reaction conditions: alcohol (1 mmol), dimethylcarbonate (1 mmol), benzyl alcohol (1 mmol), THF (1mL), 4 Å molecular sieves (0.5 g). b

methacrylate monomer which serves as a building block for the synthesis of anticholesteremic haloalkyl methacrylate polymer, or drugs bearing the nicotinate moiety with applications in the cosmetics and pharmaceutical industry (Scheme 13).44a,45 Acylation of a tertiary alcohol, 1-adamantanol, with methyl acetate required significantly higher catalyst loading and longer reaction time (Table 14). This reaction, when catalyzed by alkoxide, gave results inferior to the NHC indicating a nucleophilic rather than a basic mediated process (Table 14).46

5

Conclusions

A survey of metal and organic catalysts able to mediate the important transesterification reaction has been presented. The organic catalysts represent a very interesting class of compounds that are economically and environmentally very attractive since they eliminate the need for metal removal from the product. These, especially the NHC or their imidazolium salt precursors are commercially available and their synthesis can be achieved in short times and on a large scale.

Synthesis 2004, No. 7, 971–985


982

G. A. Grasa et al.

Table 12 ICya

Transesterification of Secondary Alcohols Catalyzed by

OH

5 mol% ICy, r.t.,

O +

R'

Entry

R''

O

molecular

Alcohol

OH

sievesb

O

% Yield (EtOAc)b,c

Entry

30

85d

65d

1

94

87

3

OH

30

93 (93)

75 (76)

30

85

76 (98)

30

85

76 (98)

OH

OH

OH

30

88 (88)

molecular sieves

Alcohol

O

R' + O

ROH

R''

OH

96

92 (97)

2

OH

93

85 (70)

3

OH

67

47

10

5

9

5

OH

OH

74 (96)

a

F

7

OH

30

81 (96)

66 (93)

8

OH

30

92 (86)

56 (86)

Reaction conditions alcohol (1mmol), acetate (1 mL), molecular sieves (0.5 g), r.t. b MeOAc/4 Å, EtOAc/5 Å. c GC yields after the indicated time (isolated yields in parentheses, after the completion of reaction).

Table 14 9

b

% Yield (EtOAc)b,c

5

MeO

O

R

% Yield (MeOAc)b,c

4

F3C

5

6

R''

R'

% Yield (MeOAc)b,c

30

5 mol% ICy, r.t., 15 min

O +

Time (min)

OH

Transesterification of Aliphatic Cyclic Alcohols – Steric

OH

ROH

R''

2

4

Table 13 Effectsa

R' +

R

O

1

REVIEW

5

OH

87 (91)

76 (89)

Transesterification of a Tertiary Alcohola OAc

OH MeOAc, 5 d, 25 °C 4 Å M. S.

10

5

92 (92)

82 (91)

OH

11

12

120

OH

OH

120

91 (89)

80 (94)

Catalyst

1

ICy

5

NR

2

ICy

10

NR

3

ICy

10

NRc

4

ICy

20

54

5

t-BuONa

1

10

6

t-BuONa

5

33

7

t-BuOK

5

35

82 (99)

92 (92)

Catalyst Loading (mol%)

% Yieldb

Entry

a

Reaction conditions: alcohol (1 mmol), acetate (1 mL), r.t., molecular sieves (0.5 g). b MeOAc/4 Å, EtOAc/5 Å. c GC yields after the indicated time (isolated yields in parentheses, after completion of reaction). d ICy (10 mol%).

a Reaction conditions: 1-adamantanol (1 mmol), methyl acetate (1 mL), molecular sieves (0.5 g). b GC yields. c 60 °C.

Synthesis 2004, No. 7, 971–985


REVIEW


983

Scheme 10 Transesterification/acylation by carbenes generated in situ. Reaction conditions: benzyl alcohol (1 mmol), methyl acetate (1 mL), imidazolium salt (3 mol%), t-BuOK (2.5 mol%), molecular sieves (0.5 g), r.t., 30 min.

Scheme 11 Transesterification/acylation of secondary alcohol by carbenes generated in situ. Reaction conditions: benzyl alcohol (1 mmol), methyl acetate (1 mL), imidazolium salt (3 mol%), t-BuOK (2.5 mol%), molecular sieves (0.5 g), r.t., 30 minutes. aGC yields.

Synthesis 2004, No. 7, 971–985


984

REVIEW

G. A. Grasa et al.

O

O

N

N

N

N

OCH3

H3C O

HO

+

O

O

O

O

OH

HO

OH

BHET N

N

N

N 9

HO

O

O

O

O

OH n

PET

Scheme 12 Transesterification/polymerization reactions catalyzed by NHCs

N

N O

O

5 mol% ICy +

O

O

HO(CH2)11Br

+

O(CH2)11Br

H

THF, r.t., 15 min 85%

HO

O

N

O

O OMe

2.5 mol% ICy

N

N

97% O

4 Å M. S., r.t., THF N

O HO

N 96%

Scheme 13

Application of NHC as nucleophilic catalysts in synthesis of drug intermediates

Acknowledgment The National Science Foundation is acknowledged for partial support of the work reported herein.

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Synthesis 2004, No. 7, 971–985
