Sodium amalgam: A highly efficient reagent for the detosylation of azathiacrown ethers

Article abstract of DOI:10.1055/s-2006-926338

A simple, nearly quantitative method is demonstrated for the deprotection of tosylated mixed azathiacrown ethers using sodium amalgam. Four macrocycles, containing differing numbers of amino groups and ring sizes, were prepared using traditional cyclizati

Full text of DOI:10.1055/s-2006-926338

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756
SHORT PAPER
Sodium Amalgam: A Highly Efficient Reagent for the Detosylation of
Azathiacrown Ethers
Detosylation
o
h
f
A
zathiacr
o
i
w
n
E
th
l
e
rs ip B. Forshee, John W. Sibert*
Department of Chemistry, The University of Texas at Dallas, Richardson, TX 75083, USA
Fax +1(972)8832925; E-mail: sibertj@utdallas.edu
Received 17 July 2005; revised 6 September 2005
tected compounds on large scale. In addition, the product
Abstract: A simple, nearly quantitative method is demonstrated for
the deprotection of tosylated mixed azathiacrown ethers using sodi-
um amalgam. Four macrocycles, containing differing numbers of
amino groups and ring sizes, were prepared using traditional cy-
crown is often highly crystalline allowing for its facile pu-
rification. However, this approach is limited by the appar-
ent difficulty of removing the tosyl protecting group in the
clization procedures and the described deprotection technique. presence of thioether functionalities. Classically, the detos-
Three of the macrocycles, [12]aneNS3, [14]aneNS3, and
ylation of amines is accomplished through the treatment
[15]aneN2S3, were reported previously, though either in low yields,
of the protected amine with strong acids (e.g., 30% HBr–
only in protected form, or using hazardous precursors, while the
CH3COOH, concd H2SO4) or lithium aluminum hydride
fourth, [18]aneN3S3, is a new ionophore.
at elevated temperatures for extended reaction periods.
Attempts by several different groups to use these methods
Key words: supramolecular chemistry, crown compounds, macro-
cycles, ligands, reductions
on N-tosylated azathiacrown ethers resulted in yields of
deprotected targets that are either low (10%),5 unreport-
ed,6,7 or in no product formation at all.8 Further, as noted
The broad field of macrocyclic chemistry1 is advanced, in
large part, through the preparation of new macrocyclic re-
ceptors or the discovery of more efficient routes to exist-
ing macrocycles. For example, over the past three
decades, the coordination chemistry of homoleptic thia-
crown ethers has been extensively studied due to im-
proved procedures in their synthesis.2 These sulfur-
containing host structures are of interest because of their
selectivity in forming complexes with heavy-metal ions.
In contrast, the nitrogen-containing azacrown ethers (e.g.,
cyclam and cyclen) have an affinity for cations of more in-
termediate hardness, namely transition-metal ions. A
wide range of synthetic tools has been developed for their
successful elaboration and, indeed, as a class, these are
some of the most well-studied ionophores.3 Substantially
fewer reports, however, have been published on the syn-
thesis and coordination chemistry of the heteroleptic,
mixed-donor azathiacrown ethers, macrocycles that con-
tain a combination of N and S donor atoms.4 This is reflec-
tive of the comparatively low-yielding synthetic
procedures involved in their preparation. As such, the de-
velopment of general synthetic avenues that lead to the
preparation of azathiacrown ethers will provide a platform
for their more thorough study as metal-chelating agents.
by McAuley and Subramanian,9 not only did conventional
acid and base hydrolysis fail to deprotect the singly tosyl-
ated simplest azathiacrown ether, 1-(p-tolylsulfonyl)-1-
aza-4,7-dithiacyclononane, but reductive hydrolysis (so-
dium/1-butanol) and reductive elimination with either so-
dium naphthalenide or the milder sodium anthracenide
also failed, with the latter giving product in 0–5% yield.
As a result of our recent interest in the coordination of
transition- and heavy-metal ions,10 we sought an im-
proved procedure for the detosylation of amines in the
presence of C–S bonds. Sodium amalgam has been used
as a comparatively mild, reductive desulfonylation agent
for aryl and alkyl sulfones11 and a detosylation agent for
polyamines12 and azaoxacrown ethers,13 but to the best of
our knowledge, not in the deprotection of tosylated azathi-
acrown ethers. We report here on the use of sodium amal-
gam as a general detosylation agent for N-tosylated
azathiacrown ethers.
Due to their lack of commercial availability, the starting
point for our investigation was the synthesis of a series of
N-tosylated azathiacrown macrocycles. Four protected
macrocycles were prepared with varying numbers of ami-
no groups and ethylene or propylene linkages between the
heteroatoms. Three of these crowns were chosen because
they were previously described in the literature, 10-
(p-tolylsulfonyl)-1,4,7-trithia-10-azacyclododecane (1),5
11-(p-tolylsulfonyl)-1,4,7-trithia-11-azacyclotetradecane
(2),7 and 10,13-bis(p-tolylsulfonyl)-1,4,7-trithia-10,13-
diazacyclopentadecane (3),8 but they were either depro-
tected in poor or unreported yields, or not at all. Com-
pound 4 is a new macrocycle that further demonstrates the
utility of the deprotection method described herein.
A particularly attractive synthetic route to azathiacrown
ethers involves the cyclization of oligoethylene or pro-
pylene dithiols with N-tosylated acyclic precursors to pro-
duce N-protected azathiacrown ethers. These reactions
take advantage of the commercial availability of a range
of dithiols, the nucleophilicity of the thiolate functionality
and proven methods for synthesizing the requisite N-pro-
SYNTHESIS 2006, No. 5, pp 0756–0758
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Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926338; Art ID: M04605SS
© Georg Thieme Verlag Stuttgart · New York

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SHORT PAPER
Detosylation of Azathiacrown Ethers
Table 1 Detosylation Yields for 1–4
757
S
Ts
Ts
HS
S
+
SH
N
N
S
S
Entry
Substrate
Product
Isolated
Yield (%)
Cs2CO3
DMF, 60 °C
1
98
S
NH
S
S
Ms
O
N
N
N
OMs
N
Ts Ts Ts
Ts
S
Ts
Ts
N
S
4
S
Scheme 1
2
3
98
99
S
S
NH
S
N
Ts
N
S
S
S
S
S
2% Na/Hg, Na2HPO4
MeOH, reflux, 10 h
S
S
S
S
H
S
NH
N
S
N
N
n
n
n
n
Ts
m
m
S
S
NH
1 n = 0, m = 1
2 n = 1, m = 1
3 n = 0, m = 2
4 n = 0, m = 3
5 n = 0, m = 1
6 n = 1, m = 1
7 n = 0, m = 2
8 n = 0, m = 3
Ts
Ts
Ts
S
S
S
4
96
S
N
N
S
NH
NH
S
S
Scheme 2
S
Crowns 2 and 3 were prepared from the combination of
the appropriate tosylated precursors with bis(2-mercapto-
ethyl) sulfide in the presence of Cs2CO3 using literature
procedures. Yields were consistent with those
H
N
N
Ts
reported previously (60% for 2; 50% for 3). Likewise,
compounds 1 and 4 (see Scheme 1) were synthesized in an
analogous fashion. As outlined in Scheme 2, the detosyla-
tions of 1–4 were achieved by treatment with 2% sodium
amalgam in a buffered methanolic mixture. Yields for all
four crowns tested were excellent with products realized
in greater than 95% yield without the need for additional
purification in the form of column chromatography or re-
crystallization. The individual results are summarized in
Table 1. In all cases, the reactions were run overnight (ca.
10–14 hours) and found to be complete even with sub-
strates that are poorly soluble in methanol, such as 3.
pound 7 was previously investigated,4,17 however, the synthetic pro-
cedures and spectral characterization of the free ligand, to the best
of our knowledge, have yet to be reported. As such, we include it
here.
10,13-Bis(p-tolylsulfonyl)-1,4,7-trithia-10,13-diazacyclopenta-
decane (3)
The synthesis of 3 was accomplished via the procedure of Blake et
al.;8 mp 250–252 °C.
1H NMR (270 MHz, DMSO-d6): d = 2.42 (s, 6 H, Ar-CH3), 2.71 (m,
8 H, CH2S), 3.25 (t, J = 7.5 Hz, 4 H, SCH2CH2N), 3.33 (s, 4 H,
NCH2CH2N), 7.32 (d, J = 8.0 Hz, 4 H, Ar-H), 7.73 (d, J = 8.0 Hz, 4
H, Ar-H).
13C NMR (75 MHz, DMSO-d6): d = 21.55, 30.29, 31.82, 32.04,
In summary, sodium amalgam is a highly efficient, gener-
al reagent for the deprotection of N-tosylated azathia-
crown ethers, thereby providing convenient access to a
class of macrocycles that are relatively little studied.
47.69, 50.35, 127.31, 130.57, 136.82, 144.06.
HRMS–CI: m/z [M + H]+ calcd for C24H35N2O4S5: 575.1200; found:
575.1194.
10,13,16-Tris(p-tolylsulfonyl)-1,4,7-trithia-10,13,16-triazacy-
clooctadecane (4)
Melting points were determined with an analog Mel-Temp melting
1
point apparatus and are reported uncorrected. H and 13C NMR
To a stirring mixture of Cs2CO3 (6.33 g, 19.4 mmol) in DMF (400
mL) at 60 °C was added over 12 h a solution containing bis(2-mer-
captoethyl)sulfide (1.58 g, 9.25 mmol) and O,O¢-dimesyl-N,N¢,N¢¢-
tritosyl-N,N¢¢-bis(2-oxyethyl)diethylenetriamine18 (7.50 g, 9.25
mmol) in DMF (250 mL). Once all the reagents had been added, the
reaction mixture was stirred for an additional 6 h at 60 °C. The
DMF was then removed in vacuo and the residue partitioned be-
tween CH2Cl2 and H2O. The organic layer was collected and dried
over MgSO4. Following filtration and evaporation of the solvent,
the crude reaction mixture was purified by column chromatography
(silica gel, CHCl3 as eluent) to afford 4 (2.39 g, 34% yield) as a
white crystalline solid; mp 156–158 °C.
spectra were recorded on a JEOL 270 MHz spectrometer at 295 K
in CDCl3 or DMSO-d6. High resolution mass spectra were acquired
at the Mass Spectrometry Facility of the University of Texas at Aus-
tin. Sodium amalgam (2%) was prepared by the modification14 of a
published procedure in which mercury is added to sodium metal un-
der an inert atmosphere.15 In our hands, the amalgam was safely
prepared, of reproducible consistency, air stable, and easily han-
dled. The protected macrocycles 1,5 2,7 and 38 were prepared by
procedures similar to those reported previously. The characteriza-
tion of 1 and 2 was consistent with the literature data. As spectro-
scopic data for 3 were not reported previously, these are included
here. Macrocycles 516 and 67 were prepared using alternate synthet-
ic methods by van de Water et al. and Chak et al., respectively.
Characterization data for 5 and 6 in this work are consistent with
that reported in the literature. The coordination chemistry of com-
1H NMR (270 MHz, CDCl3): d = 2.44 (s, 9 H, Ar-CH3), 2.73–2.85
(m, 12 H, CH2S), 3.24 (t, J = 7.4 Hz, 4 H, SCH2CH2N), 3.38 (s, 8
H, NCH2CH2N), 7.32 (m, 6 H, Ar-H), 7.73 (m, 6 H, Ar-H).
Synthesis 2006, No. 5, 756–758 © Thieme Stuttgart · New York

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758
P. B. Forshee, J. W. Sibert
SHORT PAPER
13C NMR (75 MHz, CDCl3): d = 21.68, 31.26, 32.77, 33.18, 50.66,
51.32, 52.11, 127.51, 130.07, 134.18, 134.91, 143.96, 144.27.
Acknowledgment
This work was supported by the Robert A. Welch Foundation
(Grant No. AT-1527).
HRMS–CI: m/z [M + H]+ calcd for C33H46N3O6S6: 772.1711; found:
772.1699.
Detosylation of Protected Azathiacrown Ethers: [12]aneNS3;
Representative Procedure (5)
References
(1) Comprehensive Supramolecular Chemistry, Vol. 1; Gokel,
G. W.; Atwood, J. L.; Davies, J. E.; MacNicol, D. D.;
Vögtle, F., Eds.; Pergamon: Oxford, 1996.
(2) (a) Cooper, S. R.; Rawle, S. C. Struct. Bonding (Berlin)
1990, 72, 1. (b) Blake, A. J.; Schröder, M. Adv. Inorg.
Chem. 1990, 35, 1.
(3) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Aza-Crown
Macrocycles, In Chemistry of Heterocyclic Compounds,
Vol. 51; Taylor, E. C., Ed.; Wiley: New York, 1993.
(4) For example, see: Glenny, M. A.; Blake, A. J.; Wilson, C.;
Schröder, M. J. Chem. Soc., Dalton Trans. 2003, 194; and
references cited therein.
(5) Tanaka, M.; Nakamura, M.; Ikeda, T.; Ikeda, K.; Ando, H.;
Shibutani, Y.; Yajima, S.; Kimura, K. J. Org. Chem. 2001,
66, 7008.
To a 100-mL round-bottomed flask containing 1 (1.00 g, 2.65
mmol), Na2HPO4 (3.01 g, 21.2 mmol), and 2% Na/Hg (30.4 g, 26.5
mmol Na) was added 30 mL of anhyd MeOH. The mixture was then
stirred at reflux overnight under an Ar atmosphere. Prior to workup,
the reaction mixture was checked by TLC to verify that no starting
material remained. After the mixture was cooled to r.t., the methan-
olic slurry was decanted from the Hg. The Hg was then washed with
MeOH and CH2Cl2 successively (20 mL each), followed each time
by decanting of the solvent. The decantate and washings were com-
bined and the solvent removed by rotary evaporation. The resultant
mixture was partitioned between CH2Cl2 and H2O. The organic lay-
er was collected and dried with MgSO4. Following filtration of the
drying agent, the filtrate was evaporated to give pure 5 (0.582 g,
98% yield) as a white crystalline solid.
Compounds 6–8 were prepared in an identical fashion as for 5 with
the yields and amounts of reagents noted below. The amount of
amalgam used is 10 equiv. Na per 1 equiv. of tosylated amine with
buffer and MeOH amounts scaled accordingly.
(6) Hart, S. M.; Boeyens, J. A. C.; Michael, J. P.; Hancock, R.
D. J. Chem. Soc., Dalton Trans. 1983, 1601.
(7) Chak, B.; McAuley, A.; Whitcombe, T. W. Inorg. Chim.
Acta 1996, 246, 349.
(8) Blake, A. J.; Lippolis, V.; Schröder, M. Acta Crystallogr.,
Sect. E: Struct. Rep. Online 2004, 60, o901.
(9) McAuley, A.; Subramanian, S. Inorg. Chem. 1990, 29, 2830.
(10) Sibert, J. W.; Forshee, P. B.; Lynch, V. Inorg. Chem. 2005,
44, 8602.
[14]aneNS3 (6)
Compound 2 (0.36 g, 0.89 mmol), 2% Na/Hg (10.1 g, 8.4 mmol
Na), Na2HPO4 (2.52 g, 17.7 mmol), CH3OH (10 mL); yield: 0.22 g
(98%).
(11) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 39, 3477.
(12) Vriesema, B. K.; Butler, J.; Kellogg, R. M. J. Org. Chem.
1984, 49, 110.
[15]aneN2S3 (7)
Compound 3 (1.00 g, 1.74 mmol), 2% Na/Hg (40.0 g, 34.8 mmol
Na), Na2HPO4 (3.95 g, 27.8 mmol), CH3OH (40 mL); yield: 0.46 g
(99%).
1H NMR (270 MHz, CDCl3): d = 2.69–2.90 (m, 20 H, CH2S,
CH2N), 1.80 (s, 2 H, NH).
13C NMR (75 MHz, CDCl3): d = 32.75, 33.41, 33.51, 48.75, 49.24.
HRMS–CI: m/z [M + H]+ calcd for C10H23N2S3: 267.1023; found:
(13) Sessler, J. L.; Sibert, J. W.; Hugdahl, J. D.; Lynch, V. Inorg.
Chem. 1989, 28, 1417.
(14) In our procedure, the reaction was performed without
external heat under an argon atmosphere with the reaction
apparatus placed in an oil bath. After initiating the reaction
by addition of a small amount of mercury to the sodium
metal, the remaining mercury was immediately and quickly
added (approx. 10–15 s total addition time) via an addition
funnel with rapid stirring at room temperature. The amounts
of reagents and reaction workup were as reported in ref. 15.
(15) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
Wiley: New York, 1967, 1030.
267.1025.
[18]aneN3S3 (8)
Compound 4 (1.00 g, 1.30 mmol), 2% Na/Hg (44.7 g, 38.9 mmol
Na), Na2HPO4 (4.41 g, 31.1 mmol), CH3OH (45 mL); yield: 0.39 g
(96%).
1H NMR (270 MHz, CDCl3): d = 2.64–2.88 (m, 24 H, CH2S,
CH2N), 1.88 (s, 3 H, NH).
(16) van de Water, L. A.; Buijs, W.; Driessen, W. L.; Reedijk, J.
New J. Chem. 2001, 25, 243.
(17) Westerby, B. C.; Juntunen, K. L.; Leggett, G. H.; Pett, V. B.;
Koenigbauer, M. J.; Purgett, M. D.; Taschner, M. J.;
Ochrymowycz, L. A.; Rorabacher, D. B. Inorg. Chem. 1991,
30, 2109.
(18) Atkins, T. J.; Richman, J. E.; Oettle, W. F. Org. Synth. 1978,
58, 86.
13C NMR (75 MHz, CDCl3): d = 32.48, 32.87, 33.21, 48.84, 48.84,
49.11.
HRMS–CI: m/z [M + H]+ calcd for C12H28N3S3: 310.1445; found:
310.1446.
Synthesis 2006, No. 5, 756–758 © Thieme Stuttgart · New York