New SiliaBond Coupling Reagents to Expedite Amide and ......Si-DCC can be used as a key reagent. N O...
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New SiliaBond ® Coupling Reagents to Expedite Amide and Ester Synthesis Geneviève Gingras*, Olivier Marion, Michel Morin and François Béland SiliCycle ® Inc., 2500 Parc-Technologique Blvd., Québec City (Québec), G1P 4S6, Canada *([email protected]) Conclusions For further information Please contact [email protected]. More information on this poster and related projects can be obtained at www.silicycle.com/silica-application-library. You may also get this poster in PDF version at www.silicycle.com/poster Worldwide Headquarters SiliCycle Inc., 2500, Parc-Technologique Blvd., Quebec City (Quebec) G1P 4S6, CANADA, Phone: 1 418.874.0054, Toll Free: 1 877.745.4292 (North America only) Fax: 1 418.874.0355, Website: www.silicycle.com, E-mail: [email protected] Acknowledgements Introduction Whether it’s in nature or in man-made materials, the amide unit seems to be an omnipresent feature. The amide bond is the defining molecular structure of proteins and peptides. In addition, a report estimates that as many as 25% of all synthetic pharmaceutical drugs contain an amide group. 1 Therefore, there is an ongoing scientific endeavor for the development of efficient amidation methodologies. 2 Usually, the amide bond formation relies on the use of an excess of toxic coupling reagents such as carbodiimides and supernucleophiles. These chemicals produce a large amount of by-products which tend to complicate the isolation and the desired amide product purification. Using a reagent linked to an insoluble material as a strategy has acquired tremendous importance since the introduction of the solid-phase synthesis concept. 3 The solid-phase reagents value for an amine coupling with a carboxylic acid lies in the elimination of the residual unwanted side-products. Other solid-supported reagents advantages include improved stability, toxic chemical immobilization, the ability to run multiple transformations in a single pot, and they can also be used in batch reactions and in flow chemistry. Although most of the work on solid-phase reagents has been done on functionalized organic polymers, inorganic supports such as silica gel offer multiple advantages. For instance, silica-linked products won’t shrink, swell or dissolve in any solvent and offer a high mechanical and thermal stability. Help yourself Please leave us your business card The authors would like to thank Ms. Stéphanie Parent and Mr. Stéphane Houle from SiliCycle Inc. for their valuable contribution to this poster. References 1) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J., J. Comb. Chem. 1999, 1, 55. 2) Montalbetti, C. A. G. N.; Falque, V., Tetrahedron 2005, 61, 10827. 3) Merrifield, R. B. J. Am Chem Soc. 1963, 85, 2149. 4) Nayar, N. K.; Hutchinson, D. R.; Martinelli, M., J. J. Org. Chem. 1997, 62, 982. 5) Williams, A.; Ibrahim, I. T., Chem. Rev. 1981, 81, 589. 6) J. Med. Chem. 2000, 2860. 7) Rich, D. H.; Singh, J., The Peptides: Analysis, Synthesis, Biology; Academic: New York, 1979, 1, 241. Results SiliaBond Carbodiimide (Si-DCC) 1,3-Dicyclohexylcarbodiimide (DCC) has arguably become the most commonly used reagent in peptide synthesis and in other amide bond-forming reactions of primary and secondary amines with carboxylic acids. 5 The major drawback associated with DCC is the formation of the urea by-product (DCU) that remains in solution with the product, necessitating additional purification. With the covalently bond DCC on silica, it is possible to avoid problematic purifications since a simple filtration is the only step needed to remove the unwanted urea by-product. Product Number: R70530B N C N Si Synthesis of Formylated Amino Acids N-formylamino acid esters are useful derivatives for preparing selected N-formylamino acids, for incorporating polyfunctional amino acids into peptides and for other useful starting material preparation. Formylated amino acids have been prepared in high yields with the use of SiliaBond DCT. H OH SiliaBond DCT, NMM CH 2 Cl 2 O R-NH 2 + N H H O R 2,4,6-Trichloro[1,3,5]triazine (cyanuric chloride) has been used as a versatile reagent in alkyl chloride and acid chloride synthesis. Also, this triazine has been especially useful as a coupling reagent for amide selective formation. 4 However, cyanuric chloride is toxic, corrosive, and is a severe eye, skin and respiratory tract irritant. By anchoring cyanuric chloride on a silica matrix, it is now possible to use this valuable reagent without worrying about its toxicity profile. SiliaBond DCT reacts in a similar manner as cyanuric chloride. In addition, excess reagent and by-product elimination is reduced to a simple filtration, which is particularly useful for projects where toxicity is a concern such as in the synthesis of active pharmaceutical ingredients (API). SiliaBond Dichlorotriazine (Si-DCT) Product Number: R52230B N H N N N Cl Cl Si Synthesis of Amide Derivatives of Indomethacin A recent report 6 has shown that indomethacin primary and secondary amide analogues are potent compounds for human COX-2 specific inhibition and Si-DCC can be used as a key reagent. N O OH O O Cl N O NH O O Cl R + H 2 N-R SiliaBond DCC, HOBt CH 2 Cl 2 Synthesis of Capsaicin Analogues The potential clinical uses of analgesics and the capsaicin peripheral anti-inflammatory effects, as well as the discovery of an ultra-potent capsaicin analogue (resiniferatoxin) has attracted much interest to the synthesis of these compounds. NH 2 R 1 OH R 2 O + H N R 1 R 2 O SiliaBond DCC, HOBt CH 2 Cl 2 Synthesis of Capsaicin Analogues Entry Product Yield a (Purity) b Entry Product Yield a (Purity) b 1 99 % ( > 98 %) 4 99 % ( > 98 %) 2 98 % ( > 98 %) 5 95 % ( > 94 %) 3 99 % ( > 98 %) 6 99 % c a Yield calculated on isolated crude product b Purity determined by GC-MS c Yield determined by GC-MS H N O H N O B r H N O H N O F H N O O H N O H O O Synthesis of Amide Derivatives of Indomethacin Entry Amine Yield a Entry Amine Yield a 1 90 % 3 94 % 2 82 % 4 78 % a Yield calculated on the isolated product after purification H 2 N H 2 N H 2 N H 2 N B r Si N + N Cl- C N Esterification Reaction Acid Alcohol Product Conversion a Acid Alcohol Product Conversion a MeOH 79 % EtOH 64 % EtOH 82 % EtOH 67 % a Conversion determined by GC-MS O O H O O H O O H O O H O O M e O O E t O O E t O O E t We have demonstrated that amides and esters can be successfully prepared in a timely manner using various SiliaBond Coupling Reagents . SiliaBond DCC has been used in the preparation of biologically relevant molecules such as derivatives of indomethacin and capsaicin analogues. Also, SiliaBond DCT has been used in the formylation of amino acids. Finally, we have developed SiliaBond EDC, a new supported reagent for amide coupling and esterification reactions. We are currently working on expanding the number of applications for these silica-supported reagents. New Product Synthesis of Formylated Amino Acids Entry Product Conversion a Entry Product Conversion a 1 > 99 % b 4 > 99 % 2 > 99 % 5 > 99 % 3 > 99 % 6 95 % a Conversion determined by GC-MS N H H O N H H O O N H H O O H N H O N H O H N H O SiliaBond Ethyl-Dimethylaminopropyl Carbodiimide (Si-EDC) Amide Coupling Reaction Esterification Reaction NH 2 OH O + + HOBt N H O SiliaBond EDC (3 eq.) N-Methylmorpholine CH 2 Cl 2 16 h, rt 1.2 eq. 1.0 eq. 0.5 eq. Yield = 99 % OH + MeOH Et 3 N, SiliaBond EDC CH 2 Cl 2 24 h, rt O OMe O Product Number: R70630B A recent literature review shows that 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (EDC) has imposed itself as one of the best reagents for amide coupling reactions. Indeed, the EDC basic tertiary amine enables the urea formed in the reaction to separate from the product by acidic aqueous extractions. 7 By attaching EDC to silica, it is possible to avoid this potentially problematic work-up without sacrificing the useful carbodiimide reactivity. In fact, SiliaBond EDC behaves in a similar fashion as EDC in solution but the by-product remains on the solid support.
Transcript of New SiliaBond Coupling Reagents to Expedite Amide and ......Si-DCC can be used as a key reagent. N O...
New SiliaBond® Coupling Reagents to ExpediteAmide and Ester Synthesis
Geneviève Gingras*, Olivier Marion,Michel Morin and François Béland
SiliCycle® Inc., 2500 Parc-Technologique Blvd.,Québec City (Québec), G1P 4S6, Canada
Conclusions
For further informationPlease contact [email protected]. More information on this poster and related projects can be obtained at www.silicycle.com/silica-application-library. You may also get this poster in PDF version at www.silicycle.com/poster
Worldwide HeadquartersSiliCycle Inc., 2500, Parc-Technologique Blvd., Quebec City (Quebec) G1P 4S6, CANADA,
Phone: 1 418.874.0054, Toll Free: 1 877.745.4292 (North America only)
Fax: 1 418.874.0355, Website: www.silicycle.com, E-mail: [email protected]
Acknowledgements
IntroductionWhether it’s in nature or in man-made materials, the amide unit seems to be an omnipresent feature. The amide bond is the defining molecular structure of proteins and peptides. In addition, a report estimates that as many as 25% of all synthetic pharmaceutical drugs contain an amide group.1 Therefore, there is an ongoing scientific endeavor for the development of efficient amidation methodologies.2 Usually, the amide bond formation relies on the use of an excess of toxic coupling reagents such as carbodiimides and supernucleophiles. These chemicals produce a large amount of by-products which tend to complicate the isolation and the desired amide product purification.
Using a reagent linked to an insoluble material as a strategy has acquired tremendous importance since the introduction of the solid-phase synthesis concept.3 The solid-phase reagents value for an amine coupling with a carboxylic acid lies in the elimination of the residual unwanted side-products. Other solid-supported reagents advantages include improved stability, toxic chemical immobilization, the ability to run multiple transformations in a single pot, and they can also be used in batch reactions and in flow chemistry. Although most of the work on solid-phase reagents has been done on functionalized organic polymers, inorganic supports such as silica gel offer multiple advantages. For instance, silica-linked products won’t shrink, swell or dissolve in any solvent and offer a high mechanical and thermal stability.
Help yourself Please leave us your business card
The authors would like to thank Ms. Stéphanie Parent andMr. Stéphane Houle from SiliCycle Inc. for their valuable contribution to this poster.
References1) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J., J. Comb. Chem. 1999, 1, 55.2) Montalbetti, C. A. G. N.; Falque, V., Tetrahedron 2005, 61, 10827.3) Merrifield, R. B. J. Am Chem Soc. 1963, 85, 2149.4) Nayar, N. K.; Hutchinson, D. R.; Martinelli, M., J. J. Org. Chem. 1997, 62, 982.5) Williams, A.; Ibrahim, I. T., Chem. Rev. 1981, 81, 589.6) J. Med. Chem. 2000, 2860.7) Rich, D. H.; Singh, J., The Peptides: Analysis, Synthesis, Biology; Academic: New York, 1979, 1, 241.
Results
SiliaBond Carbodiimide (Si-DCC)
1,3-Dicyclohexylcarbodiimide (DCC) has arguably become the most commonly used reagent in peptide synthesis and in other amide bond-forming reactions of primary and secondary amines with carboxylic acids.5 The major drawback associated with DCC is the formation of the urea by-product (DCU) that remains in solution with the product, necessitating additional purification. With the covalently bond DCC on silica, it is possible to avoid problematic purifications since a simple filtration is the only step needed to remove the unwanted urea by-product.
Product Number: R70530B
N C NSi
Synthesis of Formylated Amino Acids
N-formylamino acid esters are useful derivatives for preparing selected N-formylamino acids, for incorporating polyfunctional amino acids into peptides and for other useful starting material preparation. Formylated amino acids have been prepared in high yields with the use of SiliaBond DCT.
H OH
SiliaBond DCT, NMM CH2Cl2O
R-NH2 +NH
H
O
R
2,4,6-Trichloro[1,3,5]triazine (cyanuric chloride) has been used as a versatile reagent in alkyl chloride and acid chloride synthesis. Also, this triazine has been especially useful as a coupling reagent for amide selective formation.4 However, cyanuric chloride is toxic, corrosive, and is a severe eye, skin and respiratory tract irritant. By anchoring cyanuric chloride on a silica matrix, it is now possible to use this valuable reagent without worrying about its toxicity profile. SiliaBond DCT reacts in a similar manner as cyanuric chloride. In addition, excess reagent and by-product elimination is reduced to a simple filtration, which is particularly useful for projects where toxicity is a concern such as in the synthesis of active pharmaceutical ingredients (API).
SiliaBond Dichlorotriazine (Si-DCT)
Product Number: R52230B
NH
N
NN
Cl
ClSi
Synthesis of Amide Derivatives of Indomethacin
A recent report6 has shown that indomethacin primary and secondary amide analogues are potent compounds for human COX-2 specific inhibition andSi-DCC can be used as a key reagent.
N
O
OH
O
O Cl
N
O
NH
O
O Cl
R
+ H2N-R
SiliaBond DCC, HOBt
CH2Cl2
Synthesis of Capsaicin Analogues
The potential clinical uses of analgesics and the capsaicin peripheral anti-inflammatory effects, as well as the discovery of an ultra-potent capsaicin analogue (resiniferatoxin) has attracted much interest to the synthesis of these compounds.
NH2
R1
OH R2
O
+ HN
R1
R2
O
SiliaBond DCC, HOBt
CH2Cl2
Synthesis of Capsaicin Analogues
Entry Product Yielda
(Purity)b
Entry Product Yielda
(Purity)b
1 99 % (>98 %) 4 99 % (>98 %)
2 98 % (>98 %) 5 95 % (>94 %)
3 99 % (>98 %) 6 99 %c
a Yield calculated on isolated crude productb Purity determined by GC-MSc Yield determined by GC-MS
HN
O
HN
OBr
HN
O
HN
O
F
HN
O
O
HN
O
HO
O
Synthesis of Amide Derivatives of Indomethacin
Entry Amine Yielda Entry Amine Yielda
1 90 % 3 94 %
2 82 % 4 78 %
a Yield calculated on the isolated product after purification
H2N
H2N
H2N
H2N BrSi
N+ NCl-
C N
Esterification Reaction
Acid Alcohol Product Conversiona Acid Alcohol Product Conversiona
MeOH 79 % EtOH 64 %
EtOH 82 % EtOH 67 %
aConversion determined by GC-MS
O
OH
O
OH
O
OH
O
OH
O
OMe
O
OEt
O
OEt
O
OEt
We have demonstrated that amides and esters can be successfully prepared in a timely manner using various SiliaBond Coupling Reagents.
SiliaBond DCC has been used in the preparation of biologically relevant molecules such as derivatives of indomethacin and capsaicin analogues. Also, SiliaBond DCT has been used in the formylation of amino acids. Finally, we have developed SiliaBond EDC, a new supported reagent for amide coupling and esterification reactions. We are currently working on expanding the number of applications for these silica-supported reagents.
New Product
Synthesis of Formylated Amino Acids
Entry Product Conversiona Entry Product Conversiona
1 >99 %b 4 >99 %
2 >99 % 5 >99 %
3 >99 % 6 95 %
a Conversion determined by GC-MS
NH
H
O
NH
H
O
ONH
H
O
O
HNH
O
N
H
O
HNH
O
SiliaBond Ethyl-Dimethylaminopropyl Carbodiimide (Si-EDC)
Amide Coupling Reaction
Esterification Reaction
NH2
OH
O+ + HOBt
NH
O
SiliaBond EDC (3 eq.)N-Methylmorpholine
CH2Cl2
16 h, rt
1.2 eq. 1.0 eq. 0.5 eq. Yield = 99 %
OH+ MeOH
Et3N, SiliaBond EDC CH2Cl2
24 h, rt
O
OMe
O
Product Number: R70630B
A recent literature review shows that 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (EDC) has imposed itself as one of the best reagents for amide coupling reactions. Indeed, the EDC basic tertiary amine enables the urea formed in the reaction to separate from the product by acidic aqueous extractions.7 By attaching EDC to silica, it is possible to avoid this potentially problematic work-up without sacrificing the useful carbodiimide reactivity. In fact, SiliaBond EDC behaves in a similar fashion as EDC in solution but the by-product remains on the solid support.
