Scandium triflate as an efficient and recyclable catalyst for the deprotection of tert-butyl aryl sulfonamides

Article abstract of DOI:10.1081/SCC-200048949

A mild and efficient method for deprotection of tert-butyl sulfonamide groups utilizing Sc(OTf)₃ as deprotecting reagent has been developed. A variety of tert-butyl aryl sulfonamides used under these conditions gave the corresponding primary sulfonamides in high yields. The Lewis acid catalyst could be fully recovered and reused with maintained activity after the reactions. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200048949

This article was downloaded by: [University of Toronto Libraries]
On: 22 February 2013, At: 09:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Scandium Triflate as an
Efficient and Recyclable
Catalyst for the Deprotection
of Tert‐Butyl Aryl Sulfonamides
A. K. Mahalingam a , Xiongyu Wu a , Yiqian Wan a
Mathias Alterman a
&
a Department of Organic Pharmaceutical Chemistry,
BMC, Uppsala University, P.O. Box 574, SE‐751 23,
Uppsala, Sweden
Version of record first published: 28 Jul 2007.
To cite this article: A. K. Mahalingam , Xiongyu Wu , Yiqian Wan & Mathias Alterman
(2005): Scandium Triflate as an Efficient and Recyclable Catalyst for the Deprotection
of Tert‐Butyl Aryl Sulfonamides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:3, 417-425
To link to this article: http://dx.doi.org/10.1081/SCC-200048949
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,

sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communicationsw, 35: 417–425, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048949
Scandium Triflate as an Efficient and
Recyclable Catalyst for the Deprotection
of Tert-Butyl Aryl Sulfonamides
A. K. Mahalingam, Xiongyu Wu, Yiqian Wan,
and Mathias Alterman
Department of Organic Pharmaceutical Chemistry, BMC,
Uppsala University, Uppsala, Sweden
Abstract: A mild and efficient method for deprotection of tert-butyl sulfonamide
groups utilizing Sc(OTf)3 as deprotecting reagent has been developed. A variety of
tert-butyl aryl sulfonamides used under these conditions gave the corresponding
primary sulfonamides in high yields. The Lewis acid catalyst could be fully
recovered and reused with maintained activity after the reactions.
Keywords: Scandium triflate, sulfonamide, deprotection, catalyst
Acid labile protecting groups are important in organic synthesis.[1,2] Among
them, the tert-butyl group is commonly used for protection of a large
variety of functional groups, e.g., acids,[3] alcohols,[4] phenols,[5] and sulfona-
mides.[6] The sulfonamide and acylated sulfonamide groups are of great
importance in medicinal chemistry as carboxylic acid bioisosteres[7,8] and
are widely used in many bioactive compounds, e.g., AT1 antagonists,[9]
endothelin antagonists,[10] and factor Xa antagonists.[7] In the synthetic
routes to these drugs the tert-butyl group is frequently used as protection
of the sulfonamide.[6,9,11–15] The unmasking of the sulfonamide from
the tert-butyl protection is generally executed with strong protic acids,
Received in Poland September 19, 2004
Address correspondence to Mathias Alterman, Department of Organic Pharma-
ceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23, Uppsala,
Sweden. Fax: þ46 18 4714474; E-mail: mathias.alterman@orgfarm.uu.se

418
A. K. Mahalingham et al.
e.g., HCl,[6,16] H2SO4,[17] or more commonly TFA.[1,2,9,11–15] In addition,
long reaction times are often required for full conversion, i.e., from 6 h to
18 h. These harsh conditions, when applied in a medicinal chemistry
program of complex target molecules, could sometimes be limiting to the
diversity of the structures.
Environmental concerns call for reaction processes that avoid hazardous
as well as harmful reagents and solvents.[18] The importance of catalysis for
organic transformations has been increased, since catalysts are generally
used in small quantities and often recovered and reused.[19] Lewis acid
catalyzed reactions are of great interest in synthetic organic chemistry, and
unique reactivities, selectivities, and mild reaction conditions can be
achieved.[20] Recently our group reported BCl3 as a mild and selective
Lewis acid alternative to the protic acids as a deprotection reagent for tert-
butyl solfonamides.[21] Unfortunately, BCl3, like most Lewis acids,
decompose or are deactivated in the presence of water and therefore require
a dry environment or an excess of the reagent to ensure full deprotection.
Scandium triflate is considered a new type of Lewis acid that differs from
typical Lewis acids such as AlCl3, BF3, and TiCl4.[22,23] Thus, unlike most
Lewis acids scandium triflate can act as a Lewis acid in water solutions and
does not undergo decomposition or deactivation. The water stability and solu-
bility makes the scandium triflate an ideal reagent for recycling that can be
recovered without loss of activity.[24]
We therefore felt prompted to explore the use of scandium triflate as a
recyclable and mild reagent for the deprotection of tert-butyl sulfonamides.
As a model substrate N-tert-butylthiophene-2-sulfonamide 1, encompassing
a nucleophilic aromatic ring system, was used (Scheme 1). The sulfonamide
1 is traditionally deprotected with pure TFA at ambient temperature over
night.[1,2,9,11–15] This condition was used as a starting point for our investi-
gation. With the addition of 20 mol% of scandium triflate, the reaction was
completed in 1 h at RT and gave a 90% yield (entry 1, Table 1). Different
solvents were thereafter evaluated as replacement for the strong acid, TFA.
Acetonitrile, dichloromethane, dioxane, ethyl acetate, and nitro methane
were all used with 20 mol% of scandium triflate at ambient temperature.
Notably, the highly polar nitro methane[28] was the only solvent that gave
full conversion of the substrate after 24 h (79% yield, entry 2, Table 1). The
Scheme 1.

Deprotection of Tert-Butyl Aryl Sulfonamides
419
Table 1. Deprotection of N-tert-butyl aryl sulfonamides and amides with Scandium
triflate
Temp Time Isolated yield
(8C)
Entry
Product
(h)
(%)
Mp (8C) Lit. Mp (8C)
147[5]
1a
2
rt
rt
1
24
4
90
79
146–147
3
50
92,89,95,90b
4
50
5
84
155–157 155–158[25]
179–181 178–180[26]
5
50
3
89
6
50
6
85
141–142
144[14]
7
8
9
50
50
50
4
4
3
95
92
95
165–166
124–125
169–170[7]
123[15]
176–178 178–179[20]
10
11
12
50
50
50
5
4
3
87
84
92
110–112
116[27]
110–111 103–105[25]
143–144 142–143[25]
(continued)

420
A. K. Mahalingham et al.
Table 1. Continued
Temp Time Isolated yield
(8C)
Entry
13
Product
(h)
(%)
Mp (8C) Lit. Mp (8C)
50
5
96
136–138 1138–138.5[8]
14
15
50
50
7
5
94
96
144–146 141–142[19]
108–110 119–119.6[21]
aTFA as solvent.
bYield of consecutive reactions with recycled scandium triflate.
long reaction time could be decreased if the reaction mixture was heated
slightly. At 508C the reaction was completed in 4 h and the sulfonamide 2
was isolated in 92% yield (entry 3, Table 1).
Due to the unique water stability of the scandium triflate, the catalyst
could be recovered after the reaction with a conventional water extraction
followed by concentration and drying under vacuum. The recycled Lewis
acid was then reused in a consecutive reaction. Consistent with previous
findings,[29] the recycled catalyst retained its activity and gave 2 in 89%
yield (95% the third and 90% the fourth time of recycling, entry 3, Table 1).
To examine the scope and limitation of the Lewis acid deprotection pro-
cedures a series of electron-rich and electron-deficient tert-butyl aryl sulfona-
mides were selected for evaluation. The preparative results are shown in
Table 1. All of the N-tert-butyl aryl sulfonamides provided good to
excellent yields with reaction times ranging from 3 to 7h. The reaction with
N-tert-butyl-4-acetylbenzenesulfonamide, which in our previous method
relying on BCl3 was somewhat sluggish, was now very efficient and
resulted in a good yield of the sulfonamide 8 (entry 9, Table 1). The two steri-
cally hindered tri-substituted compounds 12 and 13 were straightforwardly
obtained, although the tri-methylated compound needed a slightly longer
reaction time to obtain full conversion (entries 14 and 15, Table 1).
To verify the deprotection method on a more complex drug-like
molecule, a key intermediate in the synthesis of the ANG II agonist
L-162,313[30] was used as a test molecule (Scheme 2).

Deprotection of Tert-Butyl Aryl Sulfonamides
421
Scheme 2.
Unfortunately, the tert-butyl protected compound 14 was not soluble in
nitro methane, proven to be the most suitable solvent for the Sc(OTf)3
method, therefore a 1 : 1 mixture of nitro methane:dichloroethane was used.
Hence, an elevated temperature (1008C) and a longer reaction time (24 h)
were required for full conversion of the starting material. Despite the
increased reaction time and temperature, the reaction proceeded smoothly
and the desired target compound 15 was isolated in a high yield (85%).
In summary, a mild and high-yielding method for removal of tert-butyl
protecting group from aryl sulfonamides utilizing Sc(OTf)3 has been
developed. The reaction is not sensitive to moisture and provides an environ-
mentally friendly procedure for recycling of the catalyst with preserved
activity through several cycles.
EXPERIMENTAL
General
All of the tert-butyl protected sulfonamides were commercially available
except for the starting material to the products 7 and 9 that were synthesized
according to literature procedure.[13] All reagents were weighed in air and the
reactions were conducted under an atmosphere of air. Analytical TLC was
performed using Merck glass-backed 0.2 mm silica gel 60 F-254 plates. Visu-
alization was done with UV light and staining with anisaldehyde solution [ani-
saldehyde (5.0 mL), AcOH (3.5 mL) and H2SO4 (6.0 mL) in EtOH (200 mL)]
followed by heating. Flash column chromatography was performed on silica
gel 60 (0.04–0.63 mm, E. Merck). Infrared spectra were recorded on a
1
Perkin-Elmer Model 1605 FT-IR. H and 13C NMR spectra were recorded
on a JEOL JNM-EX 270 spectrometer at 270.2 and 67.8 MHz respectively.

422
A. K. Mahalingham et al.
Low-resolution mass spectra were recorded on a Varian GC-MS instrument
equipped with a CP-Sil 8 CB capillary column (30 m ꢀ 0.25 mm, 0.25 mm)
operating at ionization energy of 70 eV. The oven temperature was
40–3008C. Melting points were recorded on an electrothermal melting
point apparatus. All the products are known from literature and gave consist-
ent analytical data.[25–27,31–43]
General Procedure for the Deprotection of Sulfonamides with
Sc(OTf)3
Sc(OTf)3 (0.048 g, 20 mol %) was added to a solution of N-tert-butyl aryl
sulfonamide (1.0 mmol) in CH3NO2 (1.0 mL) and stirred at 508C. After com-
pletion of the reaction, solvent was evaporated and the residue was dissolved
in ethyl acetate and washed with deionized water. The organic layer was dried
over MgSO4, concentrated, and purified by silica-gel flash chromatography
using pet.ether: acetone (3–1) to afford the desired products.[25–27,31–43]
Recovery of the Sc(OTf)3
The aqueous layer was evaporated and the scandium triflate was dried under
vacuum (7 mbar, 508C, 2 h) before reuse.
ACKNOWLEDGMENT
We gratefully acknowledge support from the Swedish Foundation for
Strategic Research (SSF).
REFERENCES
1. Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2nd Ed;
John Wiley & Sons: New York, 1991; p. 473.
2. Kocienski, P. J. Protecting Groups; Thieme Medical Publisher: New York, 1994.
3. Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Total synthesis of
(+)-trachyspic acid and determination of the relative configuration. Org. Lett.
2003, 5, 857–859.
4. Chun, B. K.; Song, G. Y.; Chu, C. K. Stereocontrolled syntheses of carbocyclic
C-nucleosides and related compounds. J. Org. Chem. 2001, 66, 4852–4858.
5. Maurin, P.; Ibrahim-Ouali, M.; Santelli, M. Total synthesis of new steroids having
an aromatic A ring with a 3-OH. Tetrahedron Lett. 2001, 42, 847–849.
6. Graham, S. L.; Scholz, T. H. Preparation and utility of dianions from N-tert-
butylthiophene-2-sulfonamide. J. Org. Chem. 1991, 56, 4260–4263.

Deprotection of Tert-Butyl Aryl Sulfonamides
423
7. Patani, G. A.; LaVoie, E. J. Bioisosterism: A rational approach in drug design.
Chemical Reviews 1996, 96, 3147–3176.
8. Thornber, C. W. Isosterism and molecular modification in drug design. Chemical
Society Reviews 1979, 8, 563–580.
9. Le Bourdonnec, B.; Meulon, E.; Yous, S.; Goossens, J.; Houssin, R.; Henichart, J.
Synthesis and pharmacological evaluation of new pyrazolidine-3,5-diones as AT1
angiotensin II receptor antagonists. J. Med. Chem. 2000, 43, 2685–2697.
10. Murugesan, N.; Gu, Z.; Spergel, S.; Young, M.; Chen, P.; Mathur, A.; Leith, L.;
Hermsmeier, M.; Liu, E. C.K.; Zhang, R.; Bird, E.; Waldron, T.; Marino, A.;
Koplowitz, B.; Humphreys, W. G.; Chong, S.; Morrison, R. A.; Webb, M. L.;
Moreland, S.; Trippodo, N.; Barrish, J. C. Biphenylsulfonamide endothelin
receptor antagonists. 4. Discovery of N-[[20-[[(4,5-dimethyl-3-isoxazolyl)amino]-
sulfonyl]-4-(2-oxazolyl)[1,10-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide
(BMS-207940), a highly potent and orally active ETA selective antagonist. J. Med.
Chem. 2003, 46, 125–137.
11. Ashton, W. T.; Chang, L. L.; Flanagan, K. L.; Hutchins, S. M.; Naylor, E. M.;
Chakravarty, P. K.; Patchett, A. A.; Greenlee, W. J.; Chen, T. B.; Faust, K. A.
Triazolinone biphenylsulfonamide derivatives as orally active angiotensin II
antagonists with potent AT1 receptor affinity and enhanced AT2 affinity.
J. Med. Chem. 1994, 37, 2808–2824.
12. Chang, L. L.; Ashton, W. T.; Flanagan, K. L.; Naylor, E. M.; Chakravarty, P. K.;
Patchett, A. A.; Greenlee, W. J.; Bendesky, R. J.; Chen, T. B.; Faust, K. A.;
Kling, P. J.; Schaffer, L. W.; Schorn, T. W.; Zingar, G. J.; Chang, R. S. L.;
Lotti, V. J.; Kivlighn, S. D.; Siegel, P. K. S. Triazolinones as nonpeptide angioten-
sin II antagonists. 2. Discovery of a potent and orally active triazolinone acylsul-
fonamide. Bioorg. Med. Chem. Lett. 1994a, 4, 115–120.
13. Chang, L. L.; Ashton, W. T.; Flanagan, K. L.; Rivero, R. A.; Chen, T. B.;
O’Malley, S. S.; Zingaro, G. J.; Kivlighn, S. D.; Siegl, P. K. S.; Lotti, V. J.;
Chang, R. S. L.; Greenlee, W. J. Potent triazolinone-based angiotensin II
receptor antagonists with equivalent affinity for both the AT1 and AT2
subtypes. Bioorg. Med. Chem. Lett. 1994b, 4, 2787–2792.
14. Naylor, E. M.; Chakravarty, P. K.; Costello, C. A.; Chang, R. S.; Chen, T. B.;
Faust, K. A.; Lotti, V. J.; Kivlighn, S. D.; Zingaro, G. J.; Siegel, P. K. S.;
Wong, P. C.; Carini, D. J.; Wexler, R. R.; Patchett, A. A.; Greenlee, W. J.
Potent imidazole angiotensin II antagonists: Acyl sulfonamides and acyl
sulfamides as tetrazole replacements. Bioorg. Med. Chem. Lett. 1994, 4, 69–74.
15. Quan, M. L.; Ellis, C. D.; He, M. Y.; Liauw, A. Y.; Woerner, F. J.;
Alexander, R. S.; Knabb, R. M.; Lam, P. Y. S.; Luettgen, J. M.; Wong, P. C.;
Wright, M. R.; Wexler, R. R. Nonbenzamidine tetrazole derivatives as factor Xa
inhibitors. Bioorg. Med. Chem. Lett. 2003, 13, 369–373.
16. Han, Q.; Dominguez, C.; Stouten, P. F. W.; Park, J. M.; Duffy, D. E.;
Galemmo, R. A., Jr.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.;
Wong, P. C.; Wright, M. M.; Leuttgen, J. M.; Knabb, R. M.; Wexler, R. R.
Design, synthesis, and biological evaluation of potent and selective amidino
bicyclic factor Xa inhibitors. J. Med. Chem. 2000, 43, 4398–4415.
17. Lacey, R. N. The Acid-catalyzed heterolysis of amides with alkyl-nitrogen
fission(AAL). J. Chem. Soc. 1960, 1633–1639.
18. Anastas, P. T.; Kirchhoff, M. M. Origins, current status, and future challenges of
green chemistry. Acc. Chem. Res. 2002, 35, 686–694.

424
A. K. Mahalingham et al.
19. Trost, B. M. On inventing reactions for atom economy. Acc. Chem. Res. 2002, 35,
695–705.
20. Schinzer, D. Selectivities in Lewis Acid Promoted Reactions; Kluwer Academic:
Dordrecht, 1989.
21. Wan, Y. Q.; Wu, X. Y.; Kannan, M. A.; Alterman, M. Boron trichloride as an
efficient and selective agent for deprotection of tert-butyl aryl sulfonamides.
Tetrahedron Lett. 2003, 44, 4523–4525.
22. Longbottom, D. Scandium triflate. Synlett 1999, 2023–2023.
23. Kobayashi, S. Scandium triflate in organic synthesis. Eur. J. Org. Chem. 1999,
15–27.
24. Kobayashi, S.; Manabe, K. Green Lewis acid catalysis in organic synthesis. Pure
Appl. Chem. 2000, 72, 1373–1380.
25. Sundberg, R. J.; Pearce, B. C. 3-(3-Pyrrolyl)thiopyrrolidones as precursors of
benzo[1,2-b:4,3-b0]dipyrroles. Synthesis of structures related to the phosphodi-
esterase inhibitors PDE-I and PDE-II. J. Org. Chem. 1985, 50, 425–432.
26. Morimoto, H.; Shimadzu, H.; Kushiyama, E.; Kawanishi, H.; Hosaka, T.;
Kawase, Y.; Yasuda, K.; Kikkawa, K.; Yamauchi-Kohno, R.; Yamada, K.
Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relation-
ships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives. J. Med.
Chem. 2001, 44, 3355–3368.
27. Schreinemakers, F. A. H. Recl. Trav. Chim. Pays-Bas Belg. 1897, 16, 411–424.
28. Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. Scandium trifluorometha-
nesulfonate as an extremely active Lewis acid catalyst in acylation of alcohols
with acid anhydrides and mixed anhydrides. J. Org. Chem. 1996, 61, 4560–4567.
29. Barrett, A. G.M.; Braddock, D. C. Scandium(III) or lanthanide(III) triflates as
recyclable catalysts for the direct acetylation of alcohols with acetic acid. Chem.
Commun. 1997, 351–352.
30. Kivlighn, S. D.; Lotti, V. J.; Rivero, R. A.; Siegl, P. K. S.; Zingaro, G. J.
Preparation of thiophene-substituted imidazo[4,5-b]pyridine angiotensin II
receptor agonists. In Brit. UK Pat. Appl.; Merck and Co., Inc.: USA, 1995;
p. 21Gb.
31. Buchi, J.; Aebi, A.; Kuhn, T.; Eichenberger, E. Synthesis and pharmacological
activity of some 4-benzenesulfonyl piperidides. Helv. Chim. Acta. 1956, 39,
1579–1586.
32. Burton, H.; Hu, P. F. Compounds related to 4,40-diaminodiphenyl sulfone. p-Aryl-
sulfonylphenylethylamines and related compounds. J. Chem. Soc. 1949, 178–181.
33. Buzas, A.; Teste, J. Chlorosulfonation of thiophenes. Bull. Soc. Chim. Fr. 1960,
798–803.
34. Chern, J. W.; Leu, Y. L.; Wang, S. S.; Jou, R.; Lee, C. F.; Tsou, P. C.; Hsu, S. C.;
Liaw, Y. C.; Lin, H. M. Synthesis and cytotoxic evaluation of substituted sulfonyl-
N-hydroxyguanidine derivatives as potential antitumor agents. J. Med. Chem.
1997, 40, 2276–2286.
35. Ekbom, A. Ber. 1902, 35, 651–653.
36. Evans, T. W.; Dehn, W. M. Arylsulfonyl derivatives of dibasic acids. J. Am. Chem.
Soc. 1930, 52, 2531–2533.
37. Gattermann, L. Ber. 1899, 32, 1136–1161.
38. Kakeya, N.; Aoki, M.; Kamada, A.; Yata, N. Biological activities of drugs. VI.
Structure-activity relation of sulfonamide carbonic anhydrase inhibitors. 1.
Chem. Pharm. Bull. 1969, 17, 1010–1018.

Deprotection of Tert-Butyl Aryl Sulfonamides
425
39. Kumler, W. D.; Strait, L. A. The ultraviolet absorption spectra and resonance in
benzene derivatives-sulfanilamide, metanilamide, p-aminobenzoic acid, benzene
sulfonamide, benzoic acid and aniline. J. Am. Chem. Soc. 1943, 65, 2349–2354.
40. Lenz, W. Ber. 1879, 12, 580–583.
41. Meyer, V.; Kreis, H. Ber. 1883, 16, 2172–2176.
42. Newton, A. Polyisopropylbenzenes. III. Sulfonyl chlorides and nitrosulfonyl
chlorides. J. Am. Chem. Soc. 1943, 65, 2439–2441.
43. Steinkopf, W.; Jacob, H.; Penz, H. Thiophene series. XXVI. Isomeric bromothio-
phenes and the constitution of thiophenedisulfonic acids. Ann. 1934, 512,
136–164.