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Mechanochemical 1,1'-carbonyldiimidazole mediated synthesis of carbamates. Marialucia Lanzillotto, Laure Konnert, Frédéric Lamaty, Jean Martinez, and Evelina Colacino ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.5b00819 • Publication Date (Web): 29 Sep 2015 Downloaded from http://pubs.acs.org on October 5, 2015

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ACS Sustainable Chemistry & Engineering

1 3

2

Mechanochemical 1,1’-carbonyldiimidazole-mediated synthesis of carbamates. 4 6

5

Marialucia Lanzillotto, Laure Konnert, Frédéric Lamaty, Jean Martinez, Evelina Colacino* 7 8 10

9

Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS – UM – ENSCM, 12

1

Université Montpellier, Campus Triolet, Place E. Bataillon, 34095 Cedex 5, France. 13

* E-mail: [email protected], Tel.: +33 (0)4 67 14 42 85; Fax: +33 (0)4 67 14 15

14

48 66 16 17 19

18

This article is dedicated to Dr. Rajender Varma on the occasion of his 65th birthday. 20 21 2

Abstract 24

1,1’-Carbonyldiimidazole (CDI) was used as an eco-friendly acylation agent for the 26

25

23

mechanochemical preparation of carbamates. The anticonvulsant N-methyl-O-benzyl 28

27

carbamate was obtained in a vibrational ball-mill, while planetary ball-mill was suitable to 29

develop a new sustainable method to access N-protected amino esters with no racemization. 31

30

Compared to the synthesis in solution, mechanochemistry proved to be a powerful tool 3

32

enhancing the reactivity of both alcohol and carbamoyl-imidazole intermediate, under mild 35

conditions, without the need of activation as usually reported for solution synthesis. This new 36

34

technology provides a sustainable method for the synthesis of carbamates using 1,1’38

37

carbonyldiimidazole. 39 40 42

41

Keywords: Mechanochemistry, Carbamates, 1,1’-Carbonyldiimidazole, Amino esters, 4

43

Protecting groups, Anticonvulsant. 45 47

46

Introduction 49

The needs to develop new green and sustainable methods and processes1 for a chemistry 50

48

‘benign by design’2,3 has led scientists in both academia and industry to ‘think chemistry 52

51

differently’, using safer reagents or solvents, diminishing the generation of toxic and nontoxic 54

53

waste and limiting solvent use.4 Mechanochemistry5-9 is a strong emerging field of research to 56

5

perform organic reactions in the absence of solvent.10-12 We have applied the ball-milling 58

technology to the preparation of active pharmaceutical ingredients (API)13-16 or food 60

59

57

additives17 starting from amino amino acid derivatives, and to disclose new eco-friendly alternatives to solvent-based chemistry, for the selective protection of N-21,22 or C-terminal19

ACS Paragon Plus Environment

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1 3

2

amino acid derivatives (respectively carbamates or esters), essential building blocks for 4

peptide synthesis.20 6

5

1,1’-Carbonyldiimidazole (CDI) is safe and versatile acyl transfert agent easy to handle, 8

7

compared to the commonly used toxic isocyanates, (tri)phosgene or chloroformates. 10

Available in kilogram quantities and cheap (3€/gram), it was successfully applied for the 1

9

preparation of carbonates, ureas, amides, urethanes, esters,21-23 or as a coupling agent for 13

12

peptide synthesis24-28 in solution. It is also a convenient reagent adopted in the pharmaceutical 15

14

industry for the large scale preparation of API29,30 in clean environmental conditions, since it 17

16

generates relatively innocuous and easy to remove by-products (imidazole and carbon 19

dioxide). Pursuing our interest in the development of eco-friendly methodologies to access 20

18

organic carbamates,21,22 known for their applications in agrochemistry,31 as pharmaceuticals32 2

21

or in synthetic chemistry as protecting group for amines,32-35 we decided to explore CDI as 24

23

the acylating agent for carbamate synthesis under mechanochemical activation. Surprisingly, 26

only one study reported the preparation of carbamates using CDI in a solvent-free process, 27

25

where the reactants were grinded with a spatula, not suitable for a scale-up perspective.36 29

28

We report herein a systematic investigation for the CDI-mediated mechanochemical 31

30

preparation of various carbamates using different primary or secondary alcohol/amine 3

32

combinations. The revisited and new synthesis of the anticonvulsant drug N-methyl-O-benzyl 35

carbamate37,38 was successful in a vibrational ball-mill, while N-protected benzyloxycarbonyl36

34

(Z)-, allyloxycarbonyl- (Alloc) or methoxycarbonyl- (Moc) amino esters were prepared in a 38

37

planetary ball-mill, with no racemisation. To the best of our knowledge, this represents the 40

39

first report on the CDI-mediated N-carbamoylation of amino esters by mechanochemistry. In 42

a green chemistry perspective, this pathway represents a further and significant advance in the 4

43

41

chemistry beyond the use of halogens (chloroformates), to access protected amino esters as 45

carbamates. 46 47 49

48

Results and Discussion 51

50

Two general procedures allow to access carbamates using CDI (Scheme 1): by reacting the 52

electrophilic carbamoyl imidazole with an alcohol (Method A)23,39 or by nucleophilic attack 54

53

of an amine on the electrophilic alkoxycarbonyl imidazole (Method B).23,36,43,44 Carbamoyl 56

5

imidazole is the non-toxic alternative to isocyanate, while imidazole carboxylic esters safely 58

replace chloroformates. 59

57

60


2

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1 3

2 METHOD A

4

METHOD B

5

O

6

R1NH2

CDI

7

R1

N H

R2OH N

8 9

Carbamoyl Imidazole

10

N

Base, or alkylating agent

O R1

N H

O

R2

O

R1NH2 (Base)

N

N

O

R2

CDI

R2OH

Imidazole carboxylic ester

1 12

Scheme 1. CDI-mediated preparation of carbamates. 14

13

These approaches gave high yields of carbamates using standard solution chemistry. 16

However, from a green chemistry point of view, the main disadvantages relies on the use of 18

17

15

excess of reagents and harmful bases (e.g. pyridine, NaH, KOH, etc.), inert atmosphere, long 19

reaction times (up to 24 h) and the use of volatile organic solvents (VOC) such as acetonitrile, 21

20

toluene, DMF, THF, for both reaction and work-up. Very recently an example of synthesis of 23

2

carbamates according to Method B (Scheme 1) was also described carrying out the second 25

step in water.36 27

26

24

In order to reduce the environmental impact of solvent-based procedures and for 28

understanding the mechanochemical behaviour and reactivity differences between amines and 30

29

alcohols, carbamate preparation was investigated using both methods and the preparation of 32

N,O-dibenzyl carbamate 1 was the benchmark using a vibrational ball-mill. Since the 34

3

31

electronic properties and/or steric effects are the same on both sides of each heteroatom, the 35

outcome of the reaction would depend on the specific reactivity displayed by each 37

36

nucleophile (amine or alcohol) attacking CDI in the first (and/or in the second) step. 39

38

Method A was investigated first: equimolar amounts of benzylamine and CDI were 41

reacted for one hour at 30 Hz in a stainless steel jar using 2 balls (5 mm Ø). The reaction was 43

42

40

monitored by HPLC, showing full conversion of the starting benzylamine. Then, benzyl 4

alcohol was added directly into the jar, together with K2CO3 (3 equiv), and the milling was 46

45

pursued for one more hour. The carbamoyl imidazole intermediate was fully converted, but 48

N,O-dibenzyl carbamate 1 was recovered only in 76% yield (determined by 1H NMR), 49

47

together with some N,N’-dibenzylurea (20%). Similar results were observed when the 51

50

CDI/benzylamine ratio was increased or when cycled milling was set up.15,19 Reducing the 53

52

milling time during the first step led to incomplete conversion of benzylamine. 5

54

To verify if N,N’-dibenzyl urea formation came from the high reactivity of benzylamine 57

in these conditions, less reactive nucleophilic amines such as potassium phthalimide or 4-nitro 58

56

aniline were used in the first step. The corresponding carbamoyl imidazoles were not 60

59

observed at all. When allylamine was used, benzyl N-allyl carbamate was not detected in the


3


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1 3

2

crude, but the corresponding N,N’-diallylurea - a potent inhibitor of tumor growth42 - was 5

4

obtained in 94% yield after precipitation in 10% aqueous citric acid. 6

Aiming to drive the reactivity of the system to prevent the formation of urea by-product, 8

7

preparation of N,O-dibenzyl carbamate 1 was investigated by reducing the vibration 10

frequency at 25 Hz for both steps. Although, the reaction time was doubled for both steps, the 1

9

yield dropped to 60 % and urea formation increased (36%, determined by 1H NMR). 13

12

Increasing the number of balls to four was detrimental, leading to N,N’-dibenzylurea with a 15

14

100% selectivity (and yield). We speculated that less violent shocks would reduce the kinetic 17

16

of formation of urea versus carbamate: stainless steel jars were replaced by less hard and 19

dense materials such as Teflon or polycarbonate. Unfortunately, the results were not 21

20

18

improved and no trace of N,O-dibenzyl carbamate 1 was detected in the crude at 30 Hz. 2

In solution, carbamoyl imidazole intermediates (Method A, Scheme 1) are not reactive 24

23

enough towards nucleophilic attack: activation either by alkylation of the distal nitrogen of 26

the imidazole nucleus43 and/or by deprotonation of the alcohols by strong inorganic bases 27

25

(NaOH or NaH 60% in mineral oil38) in the second step, along with prolonged reaction times 29

28

(up to 1 day) and heating, were necessary to afford carbamates. In contrast, 31

30

mechanochemistry allowed the preparation of carbamate 1 in a satisfying yield, in mild 3

32

conditions, and shorter reaction times, using no harmful reactants, with no need to further 35

activate the reactants. 36

34

Taking into account that (i) the strong mechanochemical activation was not suitable for 38

37

synthesis of carbamates starting from more nucleophilic amines compared with analogous 40

39

alcohol (Method A, Scheme 1) (ii) alcohols can react with CDI in the first step to afford 42

imidazole carboxylic ester (Method B, Scheme 1), changing the order of the reaction 4

43

41

sequence would be a simple alternative to overcome the limitations experimented during 45

Method A. 46 47

Again, benzyl alcohol and benzyl amine were selected as the two nucleophilic unit for 49

48

the one pot/two step reaction leading to N,O-dibenzylcarbamate 1 (Scheme 2). 50 51

O

52

Ph

53

CDI (2 equiv) Ph

54

Ph

OH

56

5

30 Hz, 15 min. 2 balls (5 mm O )

O

N 1a

N

O

NH2 (1.0 equiv ) Ph

N H

O

K2CO3 (1.0 equiv) 30 Hz, 90 min.

Ph

1

58

57

Scheme 2. Solvent-free preparation of N,O-dibenzyl carbamate 1 using vibrational ball-mill. 59 60


4

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1 3

2

Benzyloxycarbonylimidazole intermediate 1a was formed straightforwardly in only 15 5

4

minutes at 30 Hz with full conversion of the benzyl alcohol (the reaction was monitored by 6

HPLC). Benzylamine was added directly into the jar after the first step, without isolation or 8

7

purification of the imidazolyl intermediate and the mixture was ball milled further. 10

9

In the presence of a stoichiometric amount of CDI, compound 1 was formed in good 1

yield (80% determined by 1H NMR), but a by-product was detected in the crude after the first 13

12

step. Identified as dibenzylether, the impurity could be formed according to a decarboxylation 15

14

mechanism previously observed in some mechanochemical reactions.19 However, the amount 17

16

of CDI seemed to be important: increasing the quantity to 2 equivalents, in the same reaction 19

conditions at 30 Hz, the formation of dibenzylether was suppressed and N,O-dibenzyl 21

20

18

carbamate 1 was recovered in 79% yield after a simple work-up based on precipitation by 2

addition of aqueous citric acid, also effective for elimination of the excess of CDI and of two 24

23

equivalents of imidazole as salts (entry 1, Table 1). 26

25

The strong activation provided by mechanochemistry allowed to access N,O-dibenzyl 28

27

carbamate 1 starting from a relatively poor nucleophile like an alcohol, in very mild 29

conditions compared to solvent-based protocols, avoiding the use of strong bases (to generate 31

30

a more nucleophilic alcoholate), large excess of amine or the need to activate the imidazolide 3 34

carboxylic ester (by alkylating the distal nitrogen of the imidazole nucleus44,45 or by 35

displacement of the imidazole by toxic pyridinium salts46). 36

32

It is known that benzyl imidazole carboxylic ester 1a is thermally unstable and 38

37

decomposes in solution into N-benzyl imidazole with evolution of carbon dioxide, which is 40

the driving force of the side-reaction.23 This side-reaction was not observed under 42

41

39

mechanochemical conditions, as shown by the LC/MS analyses of the crude mixture for both 4

43

steps of the synthesis. 45

Since no more optimization was necessary, in order to investigate whether this approach 47

46

was of general applicability, other imidazole carboxylic esters were prepared in situ using 49

methanol, allyl alcohol or cyclohexanol in the first step and milled together with various 51

50

48

primary and secondary amines in the same mechanochemical conditions (Table 1). 52

The method proved to be general for the solvent-free preparation of carbamates: various 54

53

combinations of primary or secondary alcohols with amines (aliphatic, aromatic, primary or 56

5

secondary) reacted straightforward, leading to the corresponding carbamates in very good 58

yields. Reactions were monitored by HPLC, following the full conversion of the 60

59

57

corresponding imidazole carboxylic ester intermediates during the second step, while the final products were generally recovered pure after a very simple work–up based on precipitation by


5


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1 3

2

addition of aqueous citric acid15,18,19 (for solid carbamates) or by liquid-liquid extraction (for 5

4

liquid carbamates), using eco-friendly solvents such as dimethylcarbonate (DMC) or AcOEt. 6

This procedure allowed to reduce the costs of synthesis compared to methods in solution 8

7

(one-pot/two step reaction), with higher yields, producing non-toxic waste products (water 10 1

soluble imidazole, gaseous CO2 and potassium citrate, which is a food additive and a 12

medication) while purification by column chromatography was in general, not necessary. 13

9

Benzyloxy- and cyclohexyloxy imidazole esters (1a, 86% yield and 10a, 94% yield 15

14

respectively ) esters could also be isolated by precipitation in acidic water after the first step, 17

16

in high and comparable yields to solution synthesis (Table 1). This gives clear evidence of 19

their stability: they could be stored at room temperature without decomposition and they 21

20

18

could be also used in the next step directly, even without elimination of imidazole (one 2

equivalent) issued from the first step. 24

23

Although the steric hindrance around the imidazolyl moiety was not problematic to 26

access the imidazolide carboxylic esters from primary (entries 1-10) or secondary alcohols 28

27

25

(entries 11-13), sterically hindered tertiary alcohols such as t-BuOH or 1-adamantol were not 29

reactive at all in the first step, even in the presence of strong base (KOH) or using the 31

30

corresponding alkoxide (e.g.: t-BuOK). This behaviour is in contrast with solution 3 34

synthesis,41,47 leading to t-butyl imidazole carboxylic ester in these conditions, or by water35

assisted grinding.36 36

32

The steric hindrance might drive the reactivity of the entering amine in the second step 38

37

(entries 4, 8 and 10). Indeed, carbamates formed by reacting a secondary amine 40

39

(cyclohexylamine) led to average lower yields (entries 4, 8 and 10) compared to those 42

obtained by using primary amine as nucleophiles, on the same imidazole carboxylic ester 4

43

41

derivative. This was further confirmed by comparing the yield obtained for pair of carbamates 45

with inverted alkyl substituents on the heteroatoms: N-cyclohexyl-O-benzyl carbamate 4 47

46

(72%, entry 4) and N-benzyl-O-cyclohexyl carbamate 11 (90%, entry 11) or N-cyclohexyl-O49

allyl carbamate 8 (72%, entry 8) and N-allyl-O-cyclohexyl carbamate 12 (90%, entry 12). 51

50

48

Higher yields were obtained when the cyclohexyl group was introduced as the alcohol 52

moiety, ruling out any dependence on electronic effects on the side of the amine. 48 In fact, in 54

53

the absence of steric hindrance, the twin carbamates 2 and 6 were obtained in comparable 56

5

yields (entries 2 and 6) for inverted alkyl substituents. 57 58 59 60


6

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1 3

2

Table 1. Reaction scope for the one-pot/two step preparation of N,O-disubstituted carbamates 4

in a vibrational ball-mill.a,b 5 7

6 CDI (2.0 equiv) R1-OH

8

O R1

30 Hz, 15 min 2 balls (5 mm O )

9 10

O

O

R2NH2 (1.0 equiv) N

N

R1

K2CO3 (1.0 equiv)

O

N H

2 N

R2

CO2

30 Hz, 90 min

Potassium citrate

1a R1 = PhCH2 10a R1 = C6H11

1 12 14

13

H2O

NH

Waste after work-up

Entry

R1-OH

R2-NH2

1

PhCH2-

PhCH2-

Yield (%)c,d

Product

15 16

O

18

17

Ph

N H

O

19 20

Ph

1

79 (83)48

2

Quant. (74)49

3

Quant. (93)50

4

72 (93)51

5

100 (87)38

6

92 (70)52

7

73 (n.r.)f

8

72 (37)53

9

99 (84)54

10

41 (80)39

11

90 (81)48

O

21

2 2

CH2=CH-CH2-

Ph

N H

O

23 24

O

26

25

e

3

CH3CH2-

4

c-C6H11-

Ph

N H

O

27 28

O

30

29

Ph

N H

O

31 32

O

3

e

5 34

CH3-

Ph

N H

O

35 36

O

37 38

6

CH2=CH-CH2-

PhCH2-

O

N H

39 40

Ph

O

42

41

7

CH2=CH-CH2-

8

c-C6H11-

O

N H

43 4

O

46

45

N H

O

47 48

O

49

9 50

CH3-

PhCH2-

N H

O

51 52

Ph

O

53 54

10

c-C6H11-

N H

O

5 56

O

57 59

58

11

c-C6H11-

PhCH2-

O

N H

Ph

60


7


Page 8 of 17

1 2 3 O

4 5

12

CH2=CH-CH2-

13

CH3CH2-e

O

N H

6

12

90 (n.r.)f

13

92. (n.r.)f

7 8 9

O O

N H

1

10 a

12

Typical procedure using 5 mL stainless steel jar, 2 stainless steel balls (5 mm diameter) in a vibrational ball-

mill at 30 Hz: (step 1) alcohol (0.58 mmol) and 1,1’-carbonyldiimidazole (1.17 mmol) for 15 minutes; (step 2)

14

amine (0.58 mmol) and K2CO3 (0.58 mmol) for 90 minutes;

15

13

b

Milling load (ML) was kept constant at 81.3

c

mg/mL (see supporting information); Isolated yields after work-up (see supporting information);

17

16

Yields in

solution with miscellaneous methods; The RNH2 HCl (0.58 mmol) and K2CO3 (1.17 mmol) were used; f n.r. =

18

e

d

.

not reported.

19 20 21 2

We were pleased to find that Method B applied straightforward, also for the 23

mechanochemical preparation of N-methyl-O-benzyl carbamate 5 (entry 5), biologically 25

relevant for its anticonvulsant properties,37 in higher yield (99%) and milder reaction 27

26

24

conditions compared to solution synthesis (87%) according to Method A,38 requiring long 29

28

reaction times (18 h) and activation of the alcohol by hydrides. The nucleophilic MeNH 2 is a 30

gas at room temperature or above, thus not suitable as reactant, escaping the shocks55 during 32

31

the milling. The benzyloxycarbonylimidazole intermediate 1a (formed during the first step) 34

could react with the solid (but non nucleophilic!) methyl amine hydrochloride salt in the 36

35

3

presence of solid base K2CO3, according to a general base catalysis mechanism, as plausibly 37

suggested in Scheme 3. 38 39 40 41 42

H

43 4

B:

N H

45 N

47

46

H

B: O

N

O

49

Ph

H O

H N

- BH+

A

48

H

N

N

O B

Ph

HN

O

O

N

- BH+

N

O C

Ph

N H HN

N

O

Ph

5

B: = K2CO3 (2 equiv.)

50 51 52

Scheme 3. Plausible mechanism leading to N-methyl-O-benzyl carbamate 5. 53 54 56

5

It can be assumed that the benzyloxycarbonylimidazole ester 1a and methyl amine 58

57

hydrochloride were in close vicinity one to each other due to hydrogen bonding, enhancing 60

59

the electrophilicity of the carbonyl group (A). Helping the removal of the hydrochloride salt, the first equivalent of base will provide a small concentration of MeNH2 by deprotonation38,56


8

Page 9 of 17


1 3

2

(B) while the second equivalent will be involved in proton transfer for the benzyloxycarbonyl 4

imidazole ester 1a activation by protonation of imidazole (C).56 The plausibility of a general 5 6

base catalysis mechanism was assumed considering that no reaction was observed by the 8

7

direct reaction of the ammonium salt in the absence of base. 10

9

In most of the cases, the mechanochemical preparation of carbamates 1-13 by the 12

1

general Method B, led to higher yields compared to the syntheses in solution by using 13

miscellaneous methodologies, with the additional advantage that purification by column 15

14

chromatography was in general not necessary. 17

16

Unfortunately, hydroxylamine hydrochlorides or substituted hydrazides were not 19

reactive with benzyloxy imidazole carboxylic ester 1a in the second step, except for t-butyl 20

18

carbazate, which afforded N1-carboxylbenzyl-N2-tert-butoxycarbonyl hydrazine in moderate 21 2

(non-optimized) yield (44%), opening new perspectives for the solvent-free preparation of 24

23

hydrazines with orthogonal protecting groups on each nitrogen atom. 26

25

The methodology illustrated so far was flexible enough to prepare N-protected 28

27

benzyloxycarbonyl- (Z)-, allyloxycarbonyl- (Alloc) or methoxycarbonyl- (Moc) amino esters 29

in a one-pot/two steps fashion, just reacting the suitable alcohol with CDI in the first step, 31

30

followed by the addition of the amino ester derivative in the second step. 3

32

Although CDI has been employed to prepare carbamoyl derivatives of -amino acid 35

34

esters57-59 or nucleosides60 in solution (Method B, 50°C for 5 hours or longer), no example of 37

36

mechanochemical reaction has been described so far. 38

First attempts to prepare Z-Phe-OtBu 14 (Table 2, entry 1) in a vibrating ball-mill by 40

39

reacting benzyl alcohol and CDI in the first step, followed by addition of L-phenylalanine t42

41

butyl ester hydrochloride and K2CO3, according to the procedure illustrated so far for the 4

preparation of carbamates in Table 1, were unsuccessful. 45

43

Despite many trials, vibrating ball-mill proved to be unsuitable to promote the full 47

46

conversion of benzyloxycarbonyl imidazolide 1a intermediate. Several technical and process 49

48

parameters were investigated to drive the reaction to completion including the frequency (up 51

to 30 Hz), the milling time (up to 4 hours), the grinding materials for balls and jars (stainless 53

52

50

steel, zirconium oxide or tungsten carbide), size and number of milling balls (up to four with 54

variable diameters), or mode of operation (continuous or cycled). In all cases, unreacted 56

5

intermediate 1a remained in the crude and the Z-protected amino ester 14 was always 58

recovered in moderate yield (44%) together with the urea byproduct. Improvements were not 60

59

57

possible even when the liquid base diisopropylethylamine (DIPEA) was used instead of solid K2CO3.


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Page 10 of 17

1 2 3

Based on our previous findings15,18,19 the synthesis of Z-Phe-OtBu 14 was tested in a 5

4

planetary ball-mill, speculating that differences in pressure and stress phenomena during 6

milling could drive the reaction to completion. The best reaction conditions are illustrated in 8

7

Table 2. 9 10 1

Table 2. CDI-mediated preparation of N-protected amino ester in a planetary ball-milling.a,b 13

12

R2 14 15 16 17

R1

R1-OH 18

450 rpm, 15 min 25 balls (5 mm O ) 19 20

HCl . H2N CO2R3 (1.0 equiv)

O

CDI (2.0 equiv)

O

N

N

O R1

R2 N H

CO2R3

Carbamate derivative

Yield (%)d

DIPEA (2.0 equiv) 450 rpm, 2 h

O

21 2

25

24

23

Entry

R1-OH

L-Amino esterc

ML (mg/mL)

1

PhCH2

H-Phe-OtBu

92.3

Z-Phe-OtBu

14

94

2

H-Leu-OtBu

91.6

Z-Leu-OtBu

15

94

3

H-Cys(Bn)-OMe

92.4

Z-Cys(Bn)-OMe

16

94

4

H-Thr(OtBu)-OMe

91.3

Z-Thr(OtBu)-OMe

17

72

H-Phe-OtBu

92.6

Alloc-Phe-OtBu

18

96

6

H-Leu-OtBu

91.8

Alloc-Leu-OtBu

19

93

7

H-Cys(Bn)-OMe

98.9

Alloc-Cys(Bn)-OMe

20

94

H-Phe-OtBu

93.2

Me-Phe-OtBu

21

97

9

H-Leu-OtBu

92.0

Me-Leu-OtBu

22

87

10

H-Cys(Bn)-OMe

93.3

Me-Cys(Bn)-OMe

23

94

26 27 28 29 30 31 32 3 34 35

5 36

CH2=CHCH2

37 38 39 40 41 42

8 43 4 45

CH3e

46 48

47

50

49

a

Typical procedure using 12 mL stainless steel jar, 25 stainless steel balls (5 mm diameter) in a planetary ball-

mill at 450 rpm: (step 1) alcohol (0.58 mmol) and 1,1’-carbonyldiimidazole (1.17 mmol) for 15 minutes; (step 2)

51

L-amino ester hydrochloride salt (0.58 mmol) and DIPEA (1.17 mmol, 204 L) for 2 h;

53

52

c

b

ML = Milling Load

d

(see supporting information); Starting L-amino esters were hydrochloride salts; Isolated yields after work-up

54

(see supporting information); e (step 2) methanol (0.58 mmol) and 1,1’-carbonyldiimidazole (1.17 mmol) were

56

grinded twice by 15 minutes cycles, with a pause of 2 minutes between the two cycles.

57

5

60

59

58

Preparation of imidazole carboxylic esters in the planetary ball-mill did not require any adjustment in terms of milling time for both steps, compared to the conditions already


10

Page 11 of 17


1 3

2

optimized using the vibrating ball-mill. The alcohol and CDI were milled at 450 rpm for 15 5

4

minutes, affording the corresponding imidazolyl intermediate. In the case of volatile alcohols 6

such as methanol, that could vaporize during the milling, thus escaping the shocks,55 the 8

7

milling was set in two cycles of 15 minutes each (with a pause of two minutes in between) to 10

reduce the probability that methanol would vaporize due to the high pressure (at the contact 12

1

9

point of the shocks) and heat that might be generated during milling. In the second step, the 13

amino ester hydrochloride was added, together with K2CO3 as a base (2 equivalents). In 15

14

comparison with the previous data in Table 1, where only one equivalent of base was used, 17

16

herein, the second equivalent was necessary to deprotonate the starting amino ester to switch 19

the reactivity of the amine salt to a nucleophilic species, able to react with the imidazole 20

18

carboxylic ester intermediate. Z-Phe-OtBu 14 was obtained in 78% yield. However the use of 21 2

K2CO3 was associated to some problems related to the physical state of the mixture, which 24

23

became too sticky, hampering the milling, leading to incomplete conversion of the 26

benzyloxycarbonyl imidazole intermediate 1a, thus affecting the yield. 28

27

25

Considering that one equivalent of imidazole was generated in the mixture after the first 29

step, possibly able to deprotonate the amine presents in the form of the hydrochloride salt, and 31

30

that a second equivalent was liberated in situ during the second step, the reaction was also 3

32

tested in the absence of added base, speculating that an auto-catalyzed/base regenerating 35

system61 might occur. However, no reaction was observed between the imidazole carboxylic 36

34

ester 1a and HCl.H-Phe-OtBu, showing that imidazole (pKa = 6.95) was not basic enough to 38

37

abstract the proton from the amino ester hydrochloride (pKa = 7.11 for HCl.H-Phe-OtBu), as 40

39

the relative pKa values in solution indicated. Being aware that the reaction could proceed in 42

the presence of K2CO3 (pKa = 10.25), a liquid base having similar value of pKa was used. In 4

43

41

the presence of DIPEA (pKa = 10.5), formation of protected amino ester was straightforward 45

and the reaction went to completion, leading to Z-Phe-OtBu 14 in good yield (94%, Table 2, 47

46

entry 1). 49

48

It is worth to underline that irrespective of the pKa values, useful to compare the relative 51

basicity of two bases in solution, in the absence of solvent, the better reactivity (and yield) 52

50

using DIPEA was probably due to other specific effects similar to those evoked during liquid54

53

assisted grinding (LAG), relying on the physical state of the base (a liquid). This was also 56

5

confirmed by the results obtained when the reaction was tested in the presence of solid 58

K2CO3; carbamate was formed (78%) but the conversion of the alkoxycarbonyl imidazole 60

59

57

intermediate was lower, even after extended reaction times (6 hours).


11


Page 12 of 17

1 3

2

For all these reasons, solid K2CO3 was replaced by liquid DIPEA, a base commonly 5

4

used in peptide synthesis. This resulted in a successful choice allowing the preparation of 6

diverse Z-, Alloc- and Moc-carbamates amino esters, in very good yield after usual work up 8

7

(Table 2). The final products 14-23 displayed full orthogonality of the protecting groups. The 10

reaction was general and independent of the alcohol/amino ester combination. Surprisingly, 12

1

9

when allyl alcohol was reacted with L-H-Leu-OMe, only urea was formed, instead of the 13

desired protected amino ester (by comparison with entry 6). 15

14

It is well known that in solution CDI reacts with t-BuOH leading to t-butyl imidazole 17

16

carboxylic ester, a useful reagent for the preparation of the corresponding Boc-protected 19

amino acids.62 Again, although vibrating ball-mill was not suitable to t-butyl imidazole 21

20

18

carboxylic ester, planetary milling proved to be more effective. An excess of t-butanol or 2

potassium t-butoxide (t-BuOK) was reacted with CDI in the first step. Because of the 24

23

hindrance of the alcohol, milling time was extended to 1h (instead of 15 minutes). HPLC 26

monitoring during the first step, followed by LC/MS analyses, showed formation of the 28

27

25

corresponding t-butyl imidazole carboxylic ester intermediate. Then, in two parallel 29

experiments, either L-H-Phe-OMe or L-H-Cys(Bn)-OMe was added into the jars and milled at 31

30

450 rpm for 2 hours. The corresponding Boc-protected amino esters were obtained in low 3

32

yield (30%), due to an incomplete conversion of the imidazole intermediate, possibly due to a 35

high steric hindrance around the carbonyl undergoing the nucleophilic attack, hampering the 36

34

reaction to proceed. This aspect will be further investigated in a separate study. 38

37

Possible racemization was also investigated by chiral HPLC analyses in the case of Z40

Phe-OtBu 14 (entry 1): the reaction was found to be stereoconservative in nature with 42

41

39

43

retention of the optical purity (>99% ee),63 with promising applications of the methodology herein illustrated for the preparation of API.59 45

4

47

46

Conclusions 48 50

49

In summary, we have reported in this study a general and versatile green methodology 52

51

based on the CDI-mediated mechanochemical one-pot/two step synthesis of carbamates. It 53

was also successfully applied to the preparation of bioactive molecules (anticonvulsant benzyl 5

54

methyl carbamate 5) in a vibrating ball-mill. N-protected amino ester derivatives (Z-, Alloc57

and Moc-carbamates) were also obtained straightforward under solvent-free conditions in a 60

59

58

56

planetary ball-mill, with excellent yields, in mild conditions and with retention of optical purity. The mechanochemical reactions were higher yielding and faster compared to those in


12

Page 13 of 17


1 3

2

solution. The use of stable to air and easy to handle CDI as acyl transfer agent remains a valid 5

4

and green alternative to chloroformates, preventing the production of halogenated waste, 6

harmful to the environment. The method took also advantage of the increased reactivity of 8

7

alcohols during mechanochemical activation (preventing the use of strong bases or alkoxydes 10

like in solution synthesis), also avoiding: i) the use of hazardous reactants for the activation of 12

1

9

the imidazole carboxylic ester intermediate and, ii) the side-reactions experimented in 13

solution. In most cases, the final products were obtained after a simple and eco-friendly work15

14

up based on precipitation of the carbamates by aqueous treatment with 10% citric acid, 17

16

leading to a non-toxic waste i.e. potassium citrate, both a food additive and a drugs. We are 19

convinced that the new and green methodology herein described for the preparation of N21

20

18

protected amino esters as carbamates is a valid and general alternative to solvent-based 2

procedures. Undoubtless, ball milling opens up new perspectives and new reactivities for 24

23

future directions in organic synthesis and for the preparation of biomolecules. 25 26 28

27

Ackwoledgements. 29

One of us (M.L.L.) is grateful to the E.U. (Erasmus Placement Program, Universita` degli 31

30

studi Siena – Italy) for the fellowship. 32 34

3

Supporting Information. 36

Experimental procedures, 1H and 38

37

35

13

C spectral data of all compounds. Chiral HPLC analyses

of compound 14. This material is available free of charge via the Internet at 39

http://pubs.acs.org. 40 41 42

60

59

58

57

56

5

54

53

52

51

50

49

48

47

46

45

4

43

References (1) Anastas, P.; Heine, L. G.; Williamson, T. C. Green Chemical Syntheses and Processes Oxford University Press: New York (2000). (2) Anastas, P. T.; Kirchhoff, M. M. Origins, current status, and future challenges of green chemistry Acc. Chem. Res. 2002, 35, 686-694. (3) Anastas, P. T.; Warner, J. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998. (4) Green Chemistry: Frontiers in Benign Chemical Syntheses and Processes (Eds.: P. T. Anastas, T. C. Williamson), Oxford University Press, New York, (1999). (5) Ball Milling Towards Green Synthesis: Applications, Projects, Challenges A. Stolle and B. Ranu Eds.; RSC Green Chemistry Series (2015). (6) Stolle, A.; Szuppa, T.; Leonhardt, S. E. S.; Ondruschka, B. Ball milling in organic synthesis: solutions and challenges. Chem. Soc. Rev. 2011, 40, 2317–2329. (7) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friscic, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearhouse, W. C.; Steed, J. W.; Waddell, D. C.


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Mechanochemistry: opportunities for new and cleaner synthesis. Chem. Soc. Rev. 2012, 41, 413-447. Hernández, J.G.; Avila-Ortiz, C.G.; Juaristi, E. Useful Chemical Activation Alternatives in Solvent-Free Organic Reactions in Comprehensive Organic Synthesis, 2nd Edition, G.A. Molander & P. Knochel, Eds., Vol. 9, Oxford: Elsevier (2014); pp. 287-314. Hernández, J.G.; Juaristi, E. Recent Efforts Directed to the Development of More Sustainable Asymmetric Organocatalysis. Chem. Commun. 2012, 48, 5396-5409. Tanaka, K.; Toda, F. Solvent-free organic synthesis. Chem. Rev. 2000, 100, 1025 – 1074. Toda, F. Organic solid state reactions. Top. Curr. Chem. 2005, 254, 1 – 305. Walsh, P.J.; Li, H.; Anaya de Parrodi, C. A green chemistry approach to asymmetric Catalysis and highly concentrated reactions. Chem. Rev. 2007, 107, 2503-2545. Colacino, E.; Nun, P.; Colacino, F. M.; Martinez, J.; Lamaty, F. Solvent-free synthesis of nitrones in a ball-mill. Tetrahedron 2008, 64, 5569-5576. Bonnamour, J.; Métro, T.-X.; Martinez, J.; Lamaty, F. Environmentally benign peptide synthesis using liquid-assisted ball-milling: application to the synthesis of Leu-enkephalin. Green Chem. 2013, 15, 1116-1120. Konnert, L.; Reneaud, B.; Marcia de Figuieredo, R.; Campagne, J.-M.; Lamaty, F.; Martinez, J.; Colacino, E. Mechanochemical preparation of hydantoins from amino esters: application to the synthesis of the antiepileptic drug phenytoin. J. Org. Chem. 2014, 79, 10132-10142. Métro, T.-X.; Bonnamour, J. R., T.; Sarpoulet, J.; Martinez, J.; Lamaty, F. Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery. Chem. Comm. 2012, 48, 11781-11783. Declerck, V.; Nun, P.; J., M.; Lamaty, F. Solvent-free synthesis of peptides. Angew. Chem. Int. Ed. 2009, 48, 9318-9321. Konnert, L.; Gauliard, A.; Lamaty, F.; Martinez, J.; Colacino, E. Solventless synthesis of N-protected amino acids in a ball Mill. ACS Sustainable Chem. Eng. 2013, 1, 1186-1191. Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. Solventless mechanosynthesis of N-protected amino esters. J. Org. Chem. 2014, 79, 4008-4017. Hernández, J.G.; Juaristi, E. A Green Synthesis of alpha,beta- and beta,betaDipeptides under Solvent-Free Conditions. J. Org. Chem. 2010, 75, 7107-7111. Staab, v. H. A. Reaktionsfähige heterocyclische diamide der kohlensäure. Liebigs Ann. Chem. 1957, 609, 75-83. Staab, v. H. A. Reaktionsfähige N-carbonsäureester und N-carbonsäureamide des imidazols und triazols. Liebigs Ann. Chem. 1957, 609, 83-88. Staab, v. H. A. New methods of preparative organic chemistry IV. Syntheses using heterocyclic amides (azolides). Angew. Chem. Int. Ed. 1962, 1, 351-367. Anderson, G. W., Paul, R. N,N'-Carbonyldiimidazole, a new reagent for peptide synthesis. J. Am. Chem. Soc. 1958, 80, 4423. Paul, R.; Anderson, G. W. N,N'-Carbonyldiimidazole, a new peptide forming reagent. J. Am. Chem. Soc. 1960, 82, 4596-4600. Suppo, J.-S.; Subra, G.; Bergès, M.; Marcia de Figueiredo, R.; Campagne, J.-M. Inverse peptide synthesis via activated α-aminoesters. Angew. Chem. Int. Ed. 2014, 53, 5389–5393. Saha, A. K.; Schultz, P.; Rapoport, H. 1,1'-Carbonylbis(3-methylimidazolium) triflate: an efficient reagent for aminoacylations. J. Am. Chem. Soc. 1989, 111, 4856-4859.


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Gante, J. Peptide syntheses via N‐ (1‐ imidazolylcarbonyl)‐ and N‐ (1‐ imidazolylthiocarbonyl)‐ amino esters. Angew. Chem. Int. Ed. 1966, 5, 315. Dale, D. J.; Draper, J.; Dunn, P. J.; Hughes, M. L.; Hussain, F.; Levett, P. C.; Ward, G.; Wood, A. S. The process development of a scaleable route to the PDE5 inhibitor UK-357,903. Org. Process Res. Dev. 2002, 6, 767-772. Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. The chemical development of the commercial route to Sildenafil: a case history. Org. Process Res. Dev. 2000, 4, 17-22. The Pesticidal Manual ed. C.D.S. Thomlin, Crop. Protection Publication, Farnham, UK, 10th edn, 1994. Chaturvedi, D. Role of organic carbamates in anticancer drugs design, in chemistry and pharmacology of naturally occirring bioactive compounds ed. G. Bachmachari, Taylor &Francis Group, Boca Raton, 1st Edn, 2013. Isidro-Llobet, A.; Alvarez, M.; Albericio, F. Amino acid-protecting groups. Chem. Rev. 2009, 109, 2455-2504. Kocienski, P. J. Protective groups Thieme, Stuttgart, 3rd Edn, 2003. Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, Fourth Edition John Wiley & sons, New York (USA), 4th edn, (2007). Verma, S. K.; Ghorpade, R.; Pratap, A.; Kazushik, M. P. Solvent free, N,N′carbonyldiimidazole (CDI) mediated amidation. Tetrahedron Lett. 2012, 53, 23732376. Kung, C.-H.; Kwon, C.-H. Carbamate derivatives of felbamate as potential anticonvulsant agents. Med. Chem. Res. 2010, 19, 498-513. Duspara, P. A.; Islam, M. S.; Lough, A. J.; Batey, R. A. Synthesis and reactivity of N-alkyl carbamoylimidazoles: development of N-methyl carbamoylimidazole as a methyl isocyanate equivalent. J. Org. Chem. 2012, 77, 10362-10368. Rannard, S. P.; Davis, N. J.; Herbert, I. Synthesis of water soluble hyperbranched polyurethanes using selective activation of AB monomers. Macromolecules 2004, 2

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37, 9418-9430. D'Addona, D.; Bochet, C. G. Preparation of carbamates from amines and alcohols under mild conditions. Tetrahedron Lett. 2001, 42, 5227-5229. Feast, W. J.; Rannard, S. P.; Stoddart, A. Selective convergent synthesis of aliphatic polyurethane dendrimers. Macromolecules 2003, 36, 9704-9706. Tarnowski, G. S.; Cappuccino, J. G.; Schmid, F. A. Effect of 1,3-diallylurea and related compounds on growth of transplanted animal tumors. Cancer Res. 1967, 27, 1092-1095. Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Stanley Brown, R.; Batey, R. A. Carbamoylimidazolium and thiocarbamoylimidazolium salts: novel reagents for the synthesis of ureas, thioureas, carbamates, thiocarbamates and amides. Tetrahedron 2005, 61, 7153-7175. Watkins, B. E.; Kiely, J. S.; Rapoport, H. Synthesis of oligodeoxyribonucleotides using N-(benzyloxycarbonyl)-blocked nucleosides. J. Am. Chem. Soc. 1982, 104, 5702-5708. Vaillard, V. A.; Gonzalez, M.; Perotti, J. P.; Grau, R. J. A.; Vaillard, S. E. Method for the synthesis of N-alkyl-O-alkyl carbamates. RSC Adv. 2014, 4, 13012-13017. Heller, S. T.; Fu, T.; Sarpong, R. Dual Brønsted acid/nucleophilic activation of carbonylimidazole derivatives. Org. Lett. 2012, 14, 1970-1973. Rannard, S. P.; Davis, N. J. Controlled synthesis of asymmetric dialkyl and cyclic carbonates using the highly selective reactions of imidazole carboxylic esters. Org. Lett. 1999, 1, 933-936.


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57 58 59 60


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1 3

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For Table of Content Use Only 4 6

5

Mechanochemical 1,1’-carbonyldiimidazole-mediated synthesis of carbamates. 7 8 10

9

Marialucia Lanzillotto, Laure Konnert, Frédéric Lamaty, Jean Martinez, Evelina Colacino* 1 12 13

Synopsis 15

14

Ball-milling was used for the solvent-free mechanochemical preparation of carbamates and N17

16

protected amino esters with no racemization using CDI as acylating agent. 18 19 20 21 2 23 24 25 26 27 28 29 30 31 32 3 34 35 36 37 38 39 40 41 42 43 4 45 46 47 48 49 50 51 52 53 54 5 56 57 58 59 60


17

Mechanochemical 1,1â²-Carbonyldiimidazole ... - ACS Publications

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