Practical Considerations for the Formation of Acyl Imidazolides from

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Practical Considerations for the Formation of Acyl Imidazolides from Carboxylic Acids and N,N-Carbonyldiimidazole: The Role of Acid Catalysis Kenneth Michael Engstrom Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00121 • Publication Date (Web): 06 Aug 2018 Downloaded from http://pubs.acs.org on August 6, 2018

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Organic Process Research & Development

Practical Considerations for the Formation of Acyl Imidazolides from Carboxylic Acids and N,N’-Carbonyldiimidazole: The Role of Acid Catalysis Kenneth M. Engstrom Process Research and Development, AbbVie Inc., 1401 Sheridan Road, North Chicago, Illinois 60064, United States

ACS Paragon Plus Environment

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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TABLE OF CONTENTS GRAPHIC


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ABSTRACT.

The

conversion

of

carboxylic

acids

to

acyl

imidazolides

using

N,N’-carbonyldiimidazole (CDI) is hampered by the presence of alkali salts of the carboxylic acid, resulting in incomplete reactions, which cannot be driven to completion with excess CDI. Addition of an exogenous proton source reverses this effect. Sparging of the reaction mixture with carbon dioxide is also effective, presumably due to the formation of the carbamic acid of imidazole, which acts as a proton source. These results suggest that acyl imidazolide formation is subject to acid catalysis. The acceleration of acyl imidazolide formation using triflic acid or imidazolium triflate, as catalyst, is demonstrated.

KEYWORDS: acyl imidazolide, N,N’-carbonyldiimidazole (CDI), acid catalysis INTRODUCTION Acyl imidazolides are widely used as acylating agents, particularly for the formation of amide bonds.1 Preparation of acyl imidazolides from carboxylic acids is routinely implemented across the pharmaceutical industry for syntheses of both clinical candidates and commercial products.2 N,N’-Carbonyldiimidazole (CDI) is almost universally used to accomplish this transformation. CDI is somewhat sensitive to degradation by atmospheric moisture.3 However, it is commercially available at reasonable cost and the reaction byproducts (carbon dioxide and imidazole) are easily removed from process streams, making CDI attractive for use at large scale. Acyl imidazolide formation from carboxylic acids and CDI can generally be run to very high levels of reaction conversion, provided that enough CDI is added to account for reaction with any water present in the reaction medium. Accordingly, it came as a surprise when a previously quantitative acyl imidazolide formation, performed with 1.4 equiv CDI, would not proceed to full conversion, even upon addition of up to 2.0 equiv CDI. This change in reaction behavior


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did, however, correlate with a change in the isolation process for the carboxylic acid starting material. Because the physical properties and purity profile of the carboxylic acid starting material were not substantially different than previous batches, it was instead suspected that a portion of the carboxylic acid was present as the alkali carboxylate salt and that this was the root cause of the atypical reaction behavior. Although the negative impact of alkali carboxylate salts on acyl imidazolide formation may have been encountered previously, the phenomenon has yet to be thoroughly investigated.4 The generally accepted reaction pathway for acyl imidazolide formation, from a carboxylic acid and CDI, is shown in Scheme 1.5 A carboxylic acid and CDI react to form a mixed anhydride, which further reacts with liberated imidazole to generate the desired acyl imidazolide along with imidazole and carbon dioxide as byproducts. If the carboxylic acid in Scheme 1 is instead replaced by an alkali carboxylate salt, several of the steps along the reaction pathway may be slowed to an unacceptable rate, leading to aberrant reaction conversion results. Herein are described investigations of this hypothesis, which not only demonstrate why the formation of acyl imidazolides using CDI is hampered by the presence of alkali carboxylate salts, but also demonstrates that acyl imidazolide formation itself can be accelerated through acid catalysis. Scheme 1. Reaction pathway for acyl imidazolide formation

RESULTS AND DISCUSSION


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Due to the proprietary nature of the carboxylic acid discussed in the introduction, all studies were replicated using 2-methyl-2-phenylpropionic acid as a model substrate using the conditions shown in Scheme 2. Reaction conversion was assessed by HPLC at 254 nm, via derivatization of the acyl imidazolide to the corresponding methyl ester.6 Because the response factors of 2-methyl-2-phenylpropionic acid and the corresponding methyl ester are nearly equivalent at 254 nm, the measured area% conversion is approximately equivalent to mol% conversion. For this reason, area% values are used throughout this discussion. Scheme 2. 2-Methyl-2-phenylpropionic acid and its acyl imidazolide

Greater than 99% conversion of 2-methyl-2-phenylpropionic acid to the acyl imidazolide is accomplished within 5 min (Figure 1). This is in stark contrast to the behavior of sodium 2-methyl-2-phenylpropionate, which gives just 6% conversion after 2 h under otherwise identical conditions (Figure 1). 2-Methyl-2-phenylpropionic acid contaminated with either 20 mol% of the corresponding sodium or lithium carboxylate also does not reach full conversion, stalling at 94% conversion after 2 h (Figure 2).7 Addition of the anhydrous proton source imidazolium triflate, in a quantity equal to that of the alkali carboxylate, restores typical reaction conversion (Figure 3).8 Figure 1. Acyl imidazolide formation using 2-methyl-2-phenylpropionic acid versus sodium 2-methyl-2-phenylpropionate


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100 90 80 70 60

carboxylic acid

50

Na carboxylate

40 30 20 10 0 0

15

30

45

60

75

90

105

120

time (min)

Figure 2. Acyl imidazolide formation using 2-methyl-2-phenylpropionic acid containing 20 mol% alkali carboxylate

area% carboxylic acid remaining

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



15

20 mol% Na

12

20 mol% Li 9 6 3 0 0

15

30

45

60

75

90

105

120

time (min)

Figure 3. Impact of imidazolium triflate (ImTfOH) on acyl imidazolide formation of 2-methyl-2-phenylpropionic acid containing 20 mol% sodium carboxylate


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15

10 mol% ImTfOH added at 60 min 12

10 mol% ImTfOH added before CDI 9

20 mol% ImTfOH added before CDI 6 3 0 0

30

60

90

120

150

180

time (min)

Of particular note is the reaction conversion behavior shown in Figure 2, when 2-methyl-2-phenylpropionic acid contains 20 mol% alkali carboxylate. Based on the individual reaction conversion profiles shown in Figure 1, for 0 mol% and 100 mol% alkali carboxylate, one would expect a reaction of 2-methyl-2-phenylpropionic acid containing 20 mol% alkali carboxylate to quickly reach 80% conversion commensurate with the amount of carboxylic acid present, and then slow dramatically when only alkali carboxylate remains. However, as shown in Figure 2, the reactions of 2-methyl-2-phenylpropionic acid containing 20 mol% alkali carboxylate in fact rapidly exceed 80% conversion, slowing dramatically only after approximately 90% conversion has been achieved. Interestingly, this unexpected conversion behavior correlates with the evolution of carbon dioxide gas from the reaction mixture; rapid gas evolution is visually apparent within one minute of CDI addition, but slows significantly after several minutes, before becoming visually undetectable. As such, it was hypothesized that dissolved carbon dioxide was responsible for partially negating the impact of the alkali carboxylate salt on reaction conversion. This hypothesis was confirmed when an acyl imidazolide formation of 2-methyl-2-phenylpropionic acid containing 20 mol% sodium carboxylate reached 99% conversion when sparged with carbon dioxide (Figure 4). While the


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rate of amine acylation with acyl imidazolides has previously been shown to accelerate in the presence of carbon dioxide,9 this phenomenon has not been described for acyl imidazolide formation. Figure 4. Impact of carbon dioxide sparging on acyl imidazolide formation in the presence of 20 mol% sodium carboxylate


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15

20 mol% Na 12

20 mol% Na, CO2 sparge at 60 min 9 6 3 0 0

30

60

90

120

150

180

time (min)

With these experimental results in hand, a proposed pathway for acyl imidazolide formation, heavily reliant on proton transfer between reaction species and consistent with the established mechanism,5 is shown in Scheme 3. This pathway is consistent with the experimental observations as follows: 1)

Incomplete acyl imidazolide formation of carboxylic acid containing 20 mol% alkali carboxylate (Figure 2), along with restoration of typical reaction conversion behavior upon addition of 20 mol% of imidazolium triflate (Figure 3), suggests that a near stoichiometric amount of a sufficient proton source is required to enable the desired reaction. This is consistent with CDI or one or more of the reaction species shown in


8

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Scheme 3 existing in a more reactive protonated state in order to achieve a reasonable reaction rate.10 2)

Sparging with carbon dioxide enables the reaction of carboxylic acid containing 20 mol% alkali carboxylate (Figure 4) to proceed to completion, suggesting that the carbamic acid of imidazole is sufficiently acidic to ensure CDI or one or more of the reaction intermediates shown in Scheme 3 exists in a more reactive protonated state.11

3)

For carboxylic acid containing 20 mol% alkali carboxylate, reaction conversion does not slow down when the 80 mol% carboxylic acid is consumed, but proceeds significantly farther before stalling (Figure 2, Figure 3, and Figure 4). This suggests that the carbamic acid of imidazole produced via the desired reaction pathway has a sufficient lifetime to partially negate the impact of the alkali carboxylate on reaction conversion, before the carbon dioxide is irreversibly lost from the reaction mixture (Scheme 3).

Scheme 3. Proposed pathway for acyl imidazolide formation10


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O

O R

OH

N

+ N

O HO

N

N

N

R

N

NH+

O N

N

R

N

+ N

O-

R

O +

O

O N

Page 10 of 16

N

NH+

O O

N

+ HN N

N

O -

O

HN

N + CO2 (sol'n)

N2 sweep

CO2 (g)

The proposed pathway in Scheme 3 suggests that the carbamic acid of imidazole may serve as an acid catalyst during acyl imidazolide formation, allowing CDI or one or more of the reaction species to exist in a more reactive protonated state. This also suggests that acyl imidazolide formation could be accelerated, in a more general sense, via acid catalysis. While the acceleration of reaction between acyl imidazolides and various nucleophiles by both acid and carbon dioxide has been described, this concept has yet to be extended to acyl imidazolide formation.9,12 The data shown in Figure 5 demonstrates that acyl imidazolide formation is indeed accelerated by acid. Addition of 11 mol% triflic acid accelerates conversion of 2-methyl-2phenylpropionic acid into its acyl imidazolide. Because triflic acid converts rapidly to imidazolium triflate under the reaction conditions, imidazolium triflate should also be an effective catalyst. This is in fact the case, as shown in Figure 5 by the similar reaction conversion profiles obtained using either 10 mol% imidazolium triflate or 11 mol% triflic acid as catalyst.8 Figure 5. Catalysis of acyl imidazole formation with triflic acid (TfOH) and imidazolium triflate (ImTfOH) using 1.2 equiv CDI at 0.12 M in 2-MeTHF at 0 °C13


10

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100 90 80

area% conversion

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


70 60

no catalyst

50 40

11% TfOH

30 20

10 mol% ImTfOH

10 0 0

30

60

90

120

150

180

time (min)

CONCLUSIONS The presence of alkali carboxylate salts as impurities in carboxylic acids has a negative impact on conversion to acyl imidazolides using CDI. The pursuit of an explanation for this phenomenon led to a more thorough understanding of the role of protic species, including the carbamic acid of imidazole, in the desired reaction pathway. This in turn led to the demonstration that acyl imidazolide formation itself is subject to acid catalysis. While the scope of these findings is currently limited, it is likely that they are generally applicable to a range of acyl imidazolide formations. EXPERIMENTAL SECTION GENERAL All reagents and solvents were purchased from commercial sources and used without further purification. CDI was assayed prior to use.3 The sparged reaction in Figure 4 utilized a carbon dioxide gas cylinder connected via a regulator and tubing to a 16 gauge needle inserted into the


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reaction solution as close to the magnetic stir bar as possible. The flow rate was regulated such that bubbles of gas could be seen gently exiting the surface of the reaction solution. GENERAL ACYL IMIDAZOLIDE FORMATION PROCEDURE 2-Methyl-2-phenylpropionic acid (5.00 g, 30.5 mmol, 1.00 equiv) was dissolved in DMF (25 mL) in a dry, three-necked 250 mL round bottom flask containing a magnetic stirbar and temperature probe. The headspace was inerted by a flow of nitrogen attached to a vent. CDI (7.10 g of 97.3 w/w%, 42.6 mmol, 1.40 equiv) was added at ambient temperature, resulting in a mild exotherm immediately followed by a mild endotherm as carbon dioxide gas rapidly evolved from the reaction solution. Reaction conversion was determined by quenching one drop of reaction mixture into 1.5 mL 0.1 M DBU in MeOH and measuring the amount of 2-methyl-2-phenylpropionic acid and its corresponding methyl ester using the following HPLC method: Supelco Acentis Express C18, 100 × 3.0 mm, 2.7 µm particle size, 1.0 mL/min, 30 °C, 10 µL injection volume, detection at 254 nm, 90:10 0.1 v/v% aqueous H3PO4:MeCN for 1 min, then 90:10 0.1 v/v% aqueous H3PO4:MeCN to 5:95 0.1 v/v% aqueous H3PO4:MeCN over 9 min. GENERAL ALKALI CARBOXYLATE FORMATION PROCEDURE Methyl-2-phenylpropionic acid (22.45 g, 136 mmol, 1.00 equiv) was dissolved in DMF (112 mL) and reacted with 5.00 M NaOH (5.50 mL, 27.5 mmol, 20 mol%). The water was removed via distillation with EtOAc (1800 mL total, four 450 mL portions). A solution water content corresponding to roughly 0.02 equiv water was determined by direct injection of the solution into a Karl-Fischer coulometer.


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The above procedure was repeated with LiOH to generate the DMF solution of 2-methyl-2-phenylpropionic acid containing 20 mol% of the lithium carboxylate. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The author declares no competing financial interest. ACKNOWLEDGMENT Kenneth Engstrom is an employee of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. The author thanks Matthew Ravn and Seble Wagaw for valuable discussions during initial experimentation, with special thanks to Nathan Ide for valuable discussions and editorial review during manuscript preparation. REFERENCES (1) (a) Staab, H.A; Bauer, H.; Schneider, K.M. Azolides in Organic Synthesis and Biochemistry; Wiley VCH: Weinhein, 1998. (b) Montalbetti, C. A. G. N.; Falque, V. Amide Bond

Formation

and

Peptide

Coupling.

Tetrahedron

2005,

61,

10827,

https://doi.org/10.1016/j.tet.2005.08.031. (2) (a) Dunetz, J. R.; Magano, J.; Weisenburger, G.A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Rev. 2016, 20, 140, https://doi.org/10.1021/op500305s. (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, T. W.


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Analysis of the reactions used for the preparation of drug candidate molecules. Org. Biomol. Chem. 2006, 4, 2337, https://doi.org/10.1039/B602413K. (3) Engstrom, K.M.; Sheikh, A.; Ho, R.; Miller, R.M. The Stability of N,NCarbonyldiimidazole Toward Atmospheric Moisture. Org. Process Res. Dev. 2014, 18, 488, https://doi.org/10.1021/op400281h. (4) (a) Betti, M.; Genesio, E.; Panico, A.; Coccone, S.S.; Wiedenau, P. Process Development and Scale-Up for the Preparation of the 1-Methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461 Org. Process Res. Dev. 2013, 17, 1042, https://doi.org/10.1021/op400145w. (b) Theil, O.R.; Achmatowicz, M.; Bernard, C.; Wheeler, P.; Savarin, C.; Correl, T.L.; Kasparian, A.; Allgeier, A.; Bartberger, M.D.; Tan, H.; Larsen, R.D. Development of a Practical Synthesis of a p38 MAP Kinase Inhibitor. Org. Process Res. Dev. 2009, 13, 230, https://doi.org/10.1021/op800250v. (5) Staab, H.A.; Maleck, G. Über den Mechanismus der Reaktion von N.N′-Carbonyl-di-azolen mit

Carbonsäuren

zu

Carbonsäure-azoliden.

Chem.

Ber.

1966,

99,

2955,

https://doi.org/10.1002/cber.19660990931. (6) A 0.1 M DBU in MeOH solution was used for the derivatization. See the Experimental Section for full details. (7) An anhydrous solution of 2-methyl-2-phenylpropionic acid containing 20 mol% of its sodium or lithium carboxylate salt was prepared through reaction with the corresponding alkali hydroxide followed by removal of water via distillation using EtOAc. See the Experimental Section for full details.


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(8) Imidazolium triflate is attractive for use at scale because it is a non-hygroscopic, easy to handle crystalline solid. The most obvious alternatives, imidazolium chloride and triflic acid are not only both hygroscopic, but triflic acid is also highly corrosive. (9) Vaidyanathan, R.; Kalthod, V.G.; Ngo, D.P.; Manley, J.M.; Lapekas, S.P. Amidations Using N,N ‘-Carbonyldiimidazole: Remarkable Rate Enhancement by Carbon Dioxide. J. Org. Chem. 2004, 69, 2565, https://doi.org/10.1021/jo049949k. (10) An attempt was made to estimate the positions of various equilibria shown in Scheme 3 using pKa values calculated with the ChemAxon© pKa calculator. However, these values are likely not relevant given the calculator uses water as solvent. For pKa values of carboxylic acids and imidazole in DMSO, see Kolthoff, I. M.; Chantooni, K.; Bhowmlk, S. Dissociation Constants of Uncharged and Monovalent Cation Acids in Dimethyl Sulfoxide. J. Am. Chem. Soc. 1968, 90, 23, https://doi.org/10.1021/ja01003a005 and Crampton, M.R.; Robotham, I.A. Acidities of Some Substituted Ammonium Ions in Dimethyl Sulfoxide. J. Chem. Research (S) 1997, 0, 22, https://doi.org/10.1039/A606020J). (11) It was noted by a reviewer that it is also possible that carbon dioxide reacts directly with a distal nitrogen of CDI to generate a more electrophilic CDI species. (12) (a) Woodman, E.K.; Chaffey, J.G.K.; Hopes, P.A.; Hose, D.R.J.; Gilday, J.P. N,N′-Carbonyldiimidazole-Mediated Amide Coupling: Significant Rate Enhancement Achieved by Acid Catalysis with Imidazole·HCl. Org. Process Res. Dev. 2009, 13, 106, https://doi.org/10.1021/op800226b. (b) Heller, S.T.; Fu, T.; Sarpong, R. Dual Brønsted Acid/Nucleophilic Activation of Carbonylimidazole Derivatives. Org. Lett. 2012, 14, 1970, https://doi.org/10.1021/ol300339q.


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(13) The described conditions (0.12 M in 2-MeTHF at 0 °C with 1.2 equiv CDI) are significantly different than those used for the experiments shown in Figures 1 through 4 (1.2 M in DMF at ambient temperature using 1.4 equiv CDI). This change to a lower concentration, lower temperature, and reduced CDI equivalents in a less polar solvent is meant to highlight conditions under which acid catalysis would provide a practical benefit to reaction completion time.


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Practical Considerations for the Formation of Acyl Imidazolides from

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