various reagents, (d) electrochemical reduction,19,20 and (f)
metal-based reductive cleavages.21-39 Acidic deprotections
of tosylated amines use severe conditions such as H2SO4,4,5
48% HBr,6 AcOH-HClO4,7 HBr with PhOH,8 and HF-
pyridine with anisole.9 Of recent interest is a “green” phase-
transfer-catalyzed cleavage by NaOH and KOH that depro-
tects tosylated aromatic and heteroaromatic amines.16 But
for secondary amine detosylation, many of these procedures
are too harsh and/or reagent-intensive, or lack generality due
to limited substrate scope, functional group intolerance, or
demanding separations on workup.
The last and most general group, metal-based reductions,
use powerful reagents such as sodium naphthalenide,34-36
Ni(acac)2 with Grignard reagent,23 Li/NH3,30 Na/NH3,31,32
Al-Hg,25 Na-Hg,26 Red-Al,29 Na/2-propanol,21 Mg/
MeOH,36 low-valent titanium reagents,26 mischmetal with
TiCl4,27 and SmI2 with Bu3SnH.24 Although they generally
produce the desired amines in good yield, these approaches
can be difficult to scale40 and suffer from issues such as (a)
reagent instability, (b) moisture sensitivity, (c) reagent
pyrophoricity, (d) difficult removal of the reagent byproduct,
(e) the need for cryogenic reaction conditions, (f) reagent
toxicity, (g) waste handling, and (h) high cost. There remains
a need for a simple general desulfonation which harnesses
the reductive power of alkali metals without the associated
safety and cost issues.
Recently, solid alkali metal-based reductions in organic
solvents became easier with the finding that these metals can
be made significantly less pyrophoric by thermal absorption
into nanostructured silica to form the metal-silica gel (M-
SG) reagents.41-43 Herein, we report a novel method to
cleave toluenesulfonamides to amines by using M-SG.
Specifically, we have used M-SG (Stage I) where M is Na
or Na2K. The overall general transformation is analogous to
sulfonamide cleavage by alkali metal arenides and is thought
to proceed via two single-electron transfers with subsequent
cleavage to form the alkali metal amide and sulfinate salt
(Scheme 1).44-46 As described below, treatment with M-SG
Scheme 1
.
M-SG-Mediated Desulfonation of Protected
Secondary Amines (Ar ) p-Tolyl)
(19) Nyasse, B.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S.; Ragnarsson,
U. J. Org. Chem. 1999, 64, 7135
(20) Coeffard, V.; Thobie-Gautier, C.; Beaudet, I.; Le Grognec, E.;
Quintard, J.-P. Eur. J. Org. Chem. 2008, 383
.
.
(21) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Tetrahedron 1992,
48, 4475
.
(22) Bisai, A.; Singh, V. K. Tetrahedron Lett. 2007, 48, 1907
(23) Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43,
.
is a mild and general procedure to desulfonate protected
amines.
892
.
(24) Zhou, Y.; Porco, J. A., Jr.; Snyder, J. K. Org. Lett. 2007, 9, 393
(25) Carter, P.; Fitzjohn, S.; Magnus, P. J. Chem Soc., Chem. Commun.
.
Various sulfonamide substrates were investigated to
explore the scope of M-SG desulfonations (Table 1). The
reactions were conducted in ethereal solvents, typically in
THF with 2.5-5 equiv of Na2K-SG(I) at room temperature
over 8 h, and subsequently quenched with water, except
where noted.47,52 Detosylation with Na2K-SG (I) tolerates
phenyl (entries 1, 2, 4, 9, 11) and ether moieties and is
successful for both primary (entry 9) and secondary amines
(entries 1-8 and 11). The reaction’s success with the bulky
aza-cryptand (entry 8), where both HBr/AcOH and Na/NH3
methods failed, promises to be useful in our ongoing
synthetic studies of azacryptands directed to preparation of
alkalides and electrides.3 Perhaps most interesting, however,
is the (modified) reaction’s success in detosylating aziridine,
a special class of secondary amine (vide infra).
1986, 1162
.
(26) Forshee, P. B.; Sibert, J. W. Synthesis 2006, 756
.
(27) Nayak, S. K. Synthesis 2008, 1575
(28) Vellema¨e, E.; Lebedev, O.; Ma¨eorg, U. Tetrahedron Lett. 2008,
.
49, 1373
.
(29) Holmes, A. B.; Thompson, J; Baxter, A. J. G.; Dixon, J. J. Chem.
Soc., Chem. Commun. 1985, 37
(30) Wagler, T. R.; Burrows, C. J. J. Chem. Soc., Chem. Commun. 1987,
.
277
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(31) Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc.
1987, 109, 6493
(32) Akhtar, T.; Cumpstey, I. Tetrahedron Lett. 2007, 48, 8673
(33) Jordis, U.; Sauter, F.; Siddiqi, S. M.; Kuenberg, B.; Bhattacharya,
K. Synthesis 1990, 925
(34) Moser, M.; Sun, X.; Hudlicky, T. Org. Lett. 2005, 7, 5669
(35) Rinner, U.; Hudlicky, T.; Gordon, H.; Pettit, G. R Angew. Chem.,
Int. Ed. 2004, 43, 5342
(36) Burtoloso, A. C. B.; Correia, C. R. D. Tetrahedron 2008, 64, 9928
(37) Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling, S.
Tetrahedron 2000, 56, 979
(38) Larghi, E. L.; Kaufman, T. S. Tetrahedron Lett. 1997, 38, 3159
.
.
.
.
.
.
.
Modifications and Extensions. For reactions in 1,2-
dimethoxyethane (entries 7 and 9), the addition of a catalytic
amount (20 mol % relative to the sulfonamide starting
material) of ethylenediamine (EDA) accelerates N-S bond
cleavage, bringing reactions to completion in 3-4 h instead
of the 8-10 h seen without EDA.
The mesyl moiety is cleanly cleaved from 4-benzylpip-
eridine, a simple secondary amine (entry 10), suggesting that
the tosyl group’s aryl ring is not critical to the electron
capture and reductive cleavage process. Similarly, in a
preliminary study, the benzenesulfonyl group was removed
from bis(2-methoxyethyl)amine with essentially the same
efficiency as tosyl group cleavage.
.
(39) Preiml, M.; Honig, H.; Klempier, N J. Mol. Catal. B 2004, 29,
115
.
(40) Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J. P. Org. Process
Res. DeV. 2005, 9, 997.
(41) Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson,
J. E.; Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.
(42) Shatnawi, M.; Paglia, G.; Dye, J. L.; Cram, K. D.; Lefenfeld, M.;
Billinge, S. J. L. J. Am. Chem. Soc. 2007, 129, 1386.
(43) SiGNa Chemistry has developed three categories of alkali metal-
nanostructured silica materials (M-SG): Stage 0 materials are strongly
reducing pyrophoric powders. Stage I materials are nonpyrophoric, free-
flowing black powders with reactivity equivalent to neat alkali metals. Stage
II is less reducing but reacts with water to produce hydrogen at pressures
from ambient to several thousand psi. All three categories of M-SG, with
different metals and metal alloys absorbed, are available commercially.
CAUTION: With all M-SG materials, strong exothermic reactions may
occur with liquid water or sufficiently moist air.
5442
Org. Lett., Vol. 10, No. 23, 2008