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c Springer 2005
Alternative method of Boc-removal from sulfamide using silica-phenyl sulfonic acid in conjunction with microwave heating
Shahnaz Ghassemi1,∗ & Kristin Fuchs2
1 Biotage, Charlottesville, Virginia, USA; 2 University of Richmond, (∗ Author for correspondence, E-mail: firstname.lastname@example.org) Received 18 August 2004; Accepted 18 November 2004
Key words: combinatorial library, microwave assisted synthesis, silica-phenyl sulfonic acid, sulfamide
Summary A general method was used to prepare an array of unsymmetric sulfamides. This was accomplished by the stepwise addition of CSI to tert-butanol followed by the addition of amines. To increase diversity, nitrogen group of Boc-sulfamides was alkylated with alcohols using Mitsunobu reaction and Boc-group was removed using Si-TsOH. Microwave heating was used in all the steps. The ﬁnal sulfamides were released from Si-TsOH using NH3 in MeOH. Abbreviations: Boc-, tert-butyloxycarbonyl; CH2 Cl2 , DCM, methylene chloride, CF3 COOH, triﬂuoroacetic acid, CSI, chlorosulfonyl isocyanate, Si-TsOH, silica-bonded phenyl sulfonic acid In the area of combinatorial library synthesis for medicinal agents there is a constant need for new methodologies . The sulfamide compounds are noted for their broad and potent antibacterial activity . Currently, there are few sulfamides HIV-1 protease inhibitors used in chemotherapy for AIDS patients . The unsymmetric sulfamides appear to be more potent as protease inhibitors than the symmetric analogues due to the ﬂipped conformation that occurs during binding . Unfortunately, most syntheses focus on symmetric sulfamides. The few methods available for unsymmetrical compounds rely on low-yielding synthetic steps that are neither general nor selective [1, 5]. A novel transition-metal-catalyzed process for making asymmetric sulfamides that was recently reported has several limitations, especially with ortho-isomers . Even though other available methods report high yields, they either require reagents that are not readily accessible or they focus on speciﬁc structures rather than a general procedure [6–9]. The synthesis reported by Rebek et al., for example, require sulfamides with strong electron withdrawing groups . Winum and co-workers reported a novel sulfamoylating reagent 1 used in the synthesis of sulfamides . However, our study showed that using the sulfamoylating reagent added additional steps and resulted in slow, low-yielding reactions. In an effort to ﬁnd a fast and general method for sulfamide synthesis we found that microwave heating facilitates the synthesis of sulfamides. This was accomplished in onepot reaction by a stepwise addition of CSI to tert-butanol at 0 ◦ C to form the N-(tert-butoxycarbonyl) sulfamoyl chloride intermediate 2 (Scheme 1). Anilines or amines were added the reaction mixture was heated using microwave heating at 80 ◦ C for ﬁve minutes. The resulting products were isolated using normal-phase ﬂash chromatography with a good yield (Table 1). Microwave synthesis provided great improvements in increasing product yield and decreasing reaction time. 1 The microwave assisted Mitsunobu reaction was used for alkylation of Boc-sulfamides with different alcohols (Scheme 2) (Table 2) . The reaction time depended on the structure of alcohols. For example, microwave irradiation of benzyl alcohol mixture with Boc-sulfamides, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF provided JV-alkylated products in four minutes at 80 ◦ C. In the case of 2-pyridinepropanol (compounds 10, 12, 14), one minute of microwave heating was enough to complete reaction. 2 The tert-butoxycarbonyl group removal is generally carried out with triﬂuoroacetic acid either neat or in combination with CH2 Cl2 . Since CF3 COOH is volatile, harsh and corrosive, a search for an alternative method of deblocking is ongoing (Table 3).
Table 1. One-pot microwave-assisted sulfamides synthesis
were performed in the Biotage EMRYSTM Liberator microwave system in 2–5 mL reaction vials at 80 ◦ C. automated ﬂash chromatography system (Flash A 25+TM , 25 × 150 , 40–63 µm, 60 ˚ ), using ethyl acetate and hexane gradient. c Purity is calculated by HPLC (Waters, C8 4.6 × 50 mm, S-3 120 ˚ ). A d Mass spectroscopy was carried out on a Micromass R ZQ (Waters). e 1H NMR data in CDCl was collected on a 500 MHz Bruker spectrometer. 3
a Reactions b Yield of isolated product: all products were isolated on the Biotage Sp4TM
Scheme 1. Reaction and conditions: (i) tert-BuOH, CH2 Cl2 , 0 ◦ C; (ii) amine, microwave heating 80 ◦ C, minutes.
Scheme 2. Reaction and conditions: (i) R2 -OH, Ph3 P, DEAD, THF, microwave heating 80 ◦ C, (1–4) minutes.
Recently, it was reported that Amberlyst 15, a strong acidic resin, can remove the Boc-protecting group and form salts with the deprotected amines . This method has been used to facilitate the generation and puriﬁcation of amines. However, this technique requires a long reaction time (12– 24 h). We decided to explore the scope and limitations of
deblocking the BOC-group from sulfamides using silicabonded phenylsulfonic acid, and the effects of microwave heating in altering the reaction time (Scheme 3). Bocsulfamides were treated with Si-TsOH and heated by microwaves at 100 ◦ C. In all the examples, the Boc-protecting group was completely removed within ﬁve minutes. 3 Here
Table 2. N-alkylation of Boc-sulfamides
reactions were performed on the Biotage EMRYSTM Liberator microwave system using a 2.0–3.0 mmol scale in anhydrous THF with 2 eq. of alcohols. b Yield of isolated product: All products were isolated on a normal-phase ﬂash chromatography column (Flash 25+ M, ˚ 25 × 150, 40–63 µm, 60 A), using ethyl acetate and hexane gradient. c Mass spectroscopy was carried out on a Micromass R ZQ (Waters). d1 H NMR data using CDCl was collected on a 500 MHz Bruker spectrometer. 3
Scheme 3. Reaction and conditions: (i) microwave heating 100 ◦ C, 5 minutes in acetonitrile/CH2 Cl2 . (ii) 2 M NH3 /MeOH, followed by ﬂash chromatography.
we report that microwave heating with Si-TsOH signiﬁcantly shortens the Boc-removal time. The formation of salts between the sulfamide and silica bonded acid depends on subsituents on the sulfamide nitrogen (pKa of sulfamides 7–11). The desired products were released from Si-TsOH surface using NH3 /MeOH (Scheme 3). Conclusion We demonstrated a general reaction in preparation of unsymmetric Boc-sulfamides. To get more diversity, nitrogen
group of Boc-sulfamides was alkylated with alcohols using the microwave assisted Mitsunobu reaction. Also, an alternative method of Boc-removal from sulfamide was introduced using Si-TsOH in conjunction with microwave heating, Boc-de-blocked sulfamides were captured by Si-TsOH, depending on their pKa. The captured sulfamides were released from surface of Si-TsOH by using NH3 in MeOH, followed by quick ﬂash puriﬁcation. This new method of microwave-assisted, Boc-cleavage group from sulfamides facilitates the preparation and puriﬁcation of unsymmetric sulfamides.
Table 3. Microwave-assisted BOC-deblocking using Si-TsOH
a Reactions b Yield
were performed in the Biotage EMRYSTM Liberator microwave system in 2–5 mL reaction vials. of isolated product. c Mass spectroscopy was carried out on a Micromass R ZQ (Waters). d Method of deblocking see the footnote 3. c1 H NMR data was collected on a 500 MHz Bruker spectrometer.
Acknowledgments This work was carried out at Biotage, Discovery Chemistry group. We thank Dr. Mavandadi for her excellent scientiﬁc discussions, Dr. Rahn for his helpful suggestions regarding the preparation, Dr. Liu for helping with Mass Spectroscopy, Laurie Tomko for editing the English of this manuscript, Dr. Gupton and the University of Richmond for the use of its 500 MHz Bruker NMR. Notes
1. General procedure for Boc-sulfamides using microwave heating: In a typical experiment, chlorosulfonyl isocynate (0.24 mL, 2.7 mmol) was added dropwise to a solution of tert-butyl alcohol (0.26 ml, 2.7 mmol) in anhydrous dichloromethane (3 mL) in a sealed Pyrex tube under helium at 0 ◦ C. Amine
(5.5 mmol) was then added and the reaction was heated in a microwave cavity for 5 minutes at 80 ◦ C. The reaction mixture was added to a SampletTM cartridgeand puriﬁed by ﬂash chromatography. 2. General procedure for microwave assisted Mitsunobu reactions: In a typical experiment, triphenyl phosphate (43 mg, 0.4 mmol) was added to a solution of benzyl alcohol (43 µL, 0.4 mmol) and BOC-sulfamide (0.2 mmol) in anhydrous THF (4 ml). Diethyl diazenedicarboxylate (69.6 µL, 0.4 mmol) was then added dropwise and the solution was heated to 80 ◦ C in a microwave cavity for (1–4) min. The reaction mixture was added to a samplet and puriﬁed by ﬂash chromatography. 3. General procedure for microwave assisted Boc-sulfamides cleavage with Si-TsOH: Method A: Silica-bound p-toluenesulfonic acid (1.26 g, 0.96 mmol) was added to the Boc-protected sulfamide (0.32 mmol) in 1:1 acetonitrile: DCM (4 mL). The reaction was heated to 100 ◦ C in a microwave cavity for 5 min. The reaction mixture was then loaded onto a silica column. The following conditions on ﬂash chromatography yielded the desired compound – column: 25+ S; solvent A: Hexane, solvent B: EtOAc; gradient program: step 1, 0% B in 48 mL; step 2, inject 1 mL, 2M NH3 /MeOH; step 3, 0–50%B in 120 mL; step 4, 50–100% in for 100 mL; step 5, 100%B
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