A practical method for building linear and cyclic triamines from (2-trimethylsilyl)ethanesulfonamides (SES-amides)

Article abstract of DOI:10.1016/j.tet.2003.10.067

SES-chloride has been obtained in higher yield and purity by improving Weinreb's original procedure, allowing efficient access to the primary SES-amide. Linear triamines can be built conveniently from the SES-amide in high yields, with the potential for orthogonal protection. The modified Richman-Atkins cyclisation of SES-amides allows access to novel biologically interesting triazamacrocycles with combinations of three-, four-, five- and six-carbon bridges within the ring. Purification of the free macrocyclic amines by distillation greatly simplifies the workup, increasing the practicability of multi-gram scale synthesis. Although CsF sometimes provided undesirably low yields in the deprotection step, alternative fluoride sources were found to be unsuitable for the deprotection of SES-triazamacrocycles.

Full text of DOI:10.1016/j.tet.2003.10.067

Tetrahedron 59 (2003) 10165–10171
A practical method for building linear and cyclic triamines from
(2-trimethylsilyl)ethanesulfonamides (SES-amides)
*
Laurie L. Parker, Nicholas D. Gowans, Stephen W. Jones and David J. Robins
Department of Chemistry, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
Received 5 September 2003; revised 26 September 2003; accepted 23 October 2003
Abstract—SES-chloride has been obtained in higher yield and purity by improving Weinreb’s original procedure, allowing efficient access
to the primary SES-amide. Linear triamines can be built conveniently from the SES-amide in high yields, with the potential for orthogonal
protection. The modified Richman–Atkins cyclisation of SES-amides allows access to novel biologically interesting triazamacrocycles with
combinations of three-, four-, five- and six-carbon bridges within the ring. Purification of the free macrocyclic amines by distillation greatly
simplifies the workup, increasing the practicability of multi-gram scale synthesis. Although CsF sometimes provided undesirably low yields
in the deprotection step, alternative fluoride sources were found to be unsuitable for the deprotection of SES-triazamacrocycles.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Arylsulfonamides such as p-toluenesulfonamides have
traditionally been used for the cyclisation. These offer an
advantage in reactivity over other nitrogen protecting
groups by increasing the acidity of the amide protons,
with the aryl sulfonyl group stabilizing the nitrogen anions.
The bulky tosyl groups also confer a Thorpe-Ingold-type
effect on the transition state, promoting intramolecular
cyclisation rather than intermolecular oligomerisation.8,9
However, the conditions for aryl sulfonamide removal are
very harsh and, with the exception of a few commercially-
available polyazamacrocycles such as 1,4,7-triazacyclo-
nonane (tacn) and 1,4,7,11-triazacyclododecane (cyclen),
often not highly effective for these types of compounds.
Hydrolysis by heating at reflux in conc. sulfuric acid or HBr/
AcOH (with or without phenol), or reduction with lithium or
sodium in ammonia, is necessary for even partial deprotec-
tion, and sometimes decomposes the macrocycle in the
process.3,10–12 This results in low yields of macrocycles
from large-scale cyclisations, and also severely limits the
scope for varying the functionality in and around the
macrocyclic structure.
Polyazamacrocycles have a number of biologically inter-
esting applications, including the ability of their metal
complexes to catalyse the hydrolysis of DNA1 and
peptides.2 The coordination properties and thus the activity
of the complexes are affected by the number of nitrogens
and the size of the ring.3 The latter can be varied by
changing the length of the carbon chains between the
nitrogens. Triazamacrocycles which form metal complexes
with larger chelate ring sizes (e.g. 8 and 9-membered rings)
are of interest because of the unusual geometry they impart
on their coordinated metal ions.4 Linear triamines with
various carbon chain lengths including 4-, 5- and 6-carbon
bridges exhibit anti-cancer activity,5 and also have anti-
parasitic and anti-fungal properties.6 Their synthesis is
usually lengthy and/or low yielding, often requiring
purification of intermediates by column chromatography.5
Polyazamacrocycles are notoriously difficult to synthesize-
probably the most common and flexible route is the
Richman–Atkins cyclisation.7 This involves protecting a
linear polyamine as a sulfonamide, generating the di-anion
(in situ or in a separate step) via a sodium, potassium or
caesium salt, and coupling with the ditosylate of a diol
followed by intramolecular cyclisation (Scheme 1), giving
the polysulfonamide of the macrocyclic polyamine which
must be deprotected.
Recently Hoye et al. developed the use of 2-trimethylsilyl-
ethanesulfonamides for synthesis of a representative range
Keywords: polyamines; sulfonamides; polyazamacrocycles; protecting
groups.
*
Corresponding author. Tel.: þ44-141-330-4378; fax: þ44-141-330-4888;
e-mail: d.robins@chem.gla.ac.uk
Scheme 1. Richman–Atkins synthesis of azamacrocycles.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.067

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L. L. Parker et al. / Tetrahedron 59 (2003) 10165–10171
of polyazamacrocycles, but they limited their exploration of
alkyl triazamacrocycles to two commercially available
compounds, tacn and 1,5,9-triazacyclododecane (tacd).8 In
their procedure, the SES group is used to protect polyamines
as sulfonamides for cyclisation. It offers the same
advantages as traditional aryl sulfonamides, with some
added features. The reaction is carried out at room
temperature, with almost no oligomerisation observed.
The deprotection is mild enough to allow for the survival
of sensitive functionality in the compound, and also leaves
the free amine rather than the salt, eliminating the need for
conversion from the acid salt into the free base. This
conversion often reduces recovered yields due to the
solubility of these basic compounds in water.
Scheme 3. Preparation of linear triamines. Yields are given in Table 1.
Table 1. Yields for linear triamine synthesis
Here, we report our use of SES-amides in a modular
synthesis of triamines and novel triazamacrocycles, includ-
ing an improved yield in the synthesis of SES-chloride and
high purity in the isolated triazamacrocycles.
n
R¼CN
R¼CH2NH2
Free
triamine
Over 3 steps
(%)
Rept. yield
(%)
(%)
(%)
1
2
3
4a: 96
4b: 76
4c: 73
5a: 96
5b: 95
5c: 97
6a: 84
6b: 84
6c: 46
77
61
32
6014
425
2. Results and discussion
1115,16
2.1. Synthesis of SES-chloride
The synthesis of SES-chloride from vinyltrimethylsilane
(Scheme 2) was improved to give better yield and purity.
We found that by using 10 times as much DMF as
previously reported,13 we could obtain exclusively the
sulfonyl chloride 2 (free from sulfonic anhydride) in 86%
yield (compared to ,68–77% yield, after distillation from
residual sulfonic anhydride, for the published procedure).
This eliminates the need for purification other than solvent
removal and filtration, and increases the overall yield from
vinyltrimethylsilane to greater than 70%. The yield is an
improvement on previously published procedures,13 but
importantly, so is the practicability of the production of
laboratory scale amounts of 2 for general use as a
sulfonamide protecting group.
Scheme 4. Triazamacrocycle synthesis. Cyclisation and deprotection yields
and carbon chain lengths n1–n2 are given in Table 2.
the same manner as the triazamacrocycles, providing the
triamines 6a-b in higher yields than previously reported.5
Before the deprotection, the secondary SES-amide allows
for orthogonal protection of the primary amines if desired.
Scheme 2. Route to SES-chloride.
2.2. Preparation of triamines
2.3. Synthesis and deprotection of triazamacrocycles
We have used this simple access to SES-chloride to build
triamines for the synthesis of triazamacrocycles. Non-
commercially available triamines 6a and 6b were built from
SES-amide as shown in Scheme 3, and yields are given in
Table 1. 6c was also built from SES-amide for comparison.
The primary amines were then protected with SES-chloride
and the sulfonamides were cyclised as shown in Scheme 4.
The mono-SES-protected triamines could be deprotected in
Compounds 9a-f were prepared and deprotected (Scheme 4),
and the free amines were purified by Kugelrohr distillation.
10b, c, e and f are novel compounds. 10a and 10d have not
previously been reported as the free bases, only as acid
salts.4,17 The yields of cyclisation and deprotection are
reported in Table 2. The macrocycles exhibited no

L. L. Parker et al. / Tetrahedron 59 (2003) 10165–10171
Table 2. Triazamacrocycle structural details and yields
n1, n2, n3 Ring size Cyclisation yield (%) Deprotection yield (%)
10167
4. Experimental
Air- and/or moisture-sensitive experiments were carried out
under an atmosphere of N2 or Ar with glassware oven-dried
and N2 cooled. Chemicals were purchased from Aldrich
Chemical Company (Gillingham, Dorset, UK) or Lancaster
Synthesis Ltd (Morecambe, Lancs, UK) and used without
further purification. DMF was dried by three times
1,1,3
2,2,1
1,2,3
2,2,2
3,3,2
4,4,2
[3,3,5]
[4,4,3]
[3,4,5]
[4,4,4]
[5,5,4]
[6,6,4]
9a: 54
9b: 41
9c: 47
9d: 29
9e: 29
9f: 21
10a: 62
10b: 33
10c: 39
10d: 67
10e: 33
10f: 31
19
˚
sequential drying over 3 A molecular sieves. ‘Wet
DMF’ was used as purchased and not dried. Melting points
were measured with a Gallenkamp apparatus and are
uncorrected. Rf values are reported from silica gel thin-
layer chromatography. 1H (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker Avance
400 spectrometer, with chemical shift values reported on
the d scale (TMS¼0) relative to residual chloroform
(dH¼7.27 or dC¼77.2) as internal standards unless
otherwise stated. Coupling constants (J) are reported in
Hertz (Hz). Mass spectrometry was performed on a JEOL
JMS-700 spectrometer, and infrared spectra were
obtained either via solution phase (in CDCl3), or
diamond anvil (Golden Gate) IR using an FT-IR
spectrophotometer.
appreciable oligomerisation during cyclisation. We also
found that the use of dry DMF was not necessary for the
cyclisation—in fact, the yields of cyclised products as
reported here were slightly higher when DMF containing
1–2% water was used. Yields of all the cyclisations were
comparable to typical Richman–Atkins cyclisation results.
The SES-protected triamines 7a-d could be purified by
crystallization from methanol/water or isopropanol. While
the deprotection yields were variable, very high purities (as
indicated by 1H and 13C NMR spectroscopy) were obtained
in the purification by Kugelrohr distillation.
The occasionally low isolated yields in the deprotection
appeared to be the result of chelation of the free macrocycle
with Csþ residues. Upon Kugelrohr distillation, some
amount of pure amine was obtained, but a significant
amount of yellow oil remained in the original flask. It was
not possible to distill this material even at temperatures
exceeding 2508C and pressures below 0.1 mm Hg. 1H NMR
spectroscopy of the yellow material showed it still appeared
to contain mostly the macrocyclic amine. However, slight
chemical shift changes indicated that the free amine may
have complexed to residual Csþ ions. Small macrocyclic
heterocycles are known to chelate to alkali metal ions, e.g.
18-crown-6 forms a strong complex with Kþ. Also, a
‘perfect fit’ between ion size and macrocycle cavity is not
necessary for complexation to occur.18 Attempts to free the
parent amine using EDTA, or forming the HCl salt, were not
successful.
4.1. 2-(Trimethylsilylethane)sulfonyl chloride (2)
2-(Trimethylsilyl)ethane sodium sulfonate (1) was prepared
according to the procedure of Weinreb et al.,13 except the
reaction was allowed to proceed for 72 h, the salt was dried
on a rotary evaporator at 608C for 4 h, and yields obtained
were 85–92%. The preparation of sulfonyl chloride was
modified as follows:
The sulfonate salt (30.8 g, 0.151 mol) was crushed to a fine
powder in a round-bottom flask with a large stir bar. The
solid was cooled to 08C on an ice bath, and thionyl chloride
(175 mL, 0.340 mol) was added dropwise via pressure-
equalising dropping funnel fitted with an oil bubbler,
causing evolution of SO2 gas. It was essential to maintain
strong magnetic stirring throughout the addition of the
thionyl chloride to ensure even cooling and dispersion of the
sulfonate salt. Upon completion of thionyl chloride
addition, the dropping funnel was removed and N,N-
dimethylformamide (4.3 mL, 5.5 mmol) was added drop-
wise. The oil bubbler was fitted to the flask and the mixture
stirred while allowing it to warm to room temperature. After
24 h, the excess thionyl chloride was removed by rotary
evaporation (with the vacuum protected by a base trap).
Hexane (2£50 mL) was added to assist in the removal of
residual thionyl chloride. The resulting yellow paste was
stirred with hexane (250 mL) for 15 min, then filtered
through a pad of Celite, washing with more hexane
(approximately 200 mL). The hexane was removed by
rotary evaporation to give pure 2-(trimethylsilyl)ethane-
sulfonyl chloride as a yellow oil (25.7 g, 85% yield).
Spectroscopic data were identical to those reported in the
literature.13
To circumvent the problem of metal ion chelation,
alternative fluoride sources were investigated. Although
tetraalkylammonium fluorides (e.g. TBAF, TEAF, TMAF)
and KF/18-crown-6 did successfully remove the SES-
groups, it was not possible to separate their by-products
from the desired amines by Kugelrohr distillation. Other
fluoride sources (polymer-supported fluoride, NH4F2,
NH4F, HF/pyridine, 40% aqueous HF) were unsuccessful
at deprotecting the sulfonamides even under harsh con-
ditions, e.g. reflux, microwave irradiation, and sonication.
3. Conclusions
The modular synthesis of triamines from SES-amide offers
convenient access to linear and cyclic amines with control
over the carbon-bridge architecture. The improved effi-
ciency achieved in the production of SES-chloride greatly
increases the practicality of the use of this protecting group.
Further studies of the complexation properties of the novel
macrocycles are in progress, as is the biological evaluation
of their ability to act as unnatural polyamine analogues.
4.1.1. 2-(Trimethylsilyl)ethanesulfonamide (3). Ammonia
gas, produced by gentle warming (30–408C) of 8 M
aqueous ammonia solution, was bubbled through a stirred
solution of 2 (11.0 g, 55 mmol) in dichloromethane
(100 mL) at 08C. After 2 h the reaction mixture was filtered,

10168
L. L. Parker et al. / Tetrahedron 59 (2003) 10165–10171
washed with water, dried (MgSO4) and concentrated to
give 3 as a cream crystalline solid (8.73 g, 88% yield)
mp¼85–888C; IR: nmax (Golden Gate) 1147, 1271, 1327,
4.3. General procedure for the synthesis of 5a-c
4.3.1. 6-(2-(Trimethylsilyl)ethanesulfonyl)-1,6,11-tri-
azaundecane (5a). Compound 4a (3.28 g, 10.4 mmol)
was dissolved in anhydrous THF (20 mL) in an oven-dried
flask. Borane–THF (1 M in THF, 8 equiv.) was added via
syringe and the solution heated at reflux for 2 h. The excess
borane was quenched with 6 M HCl and methanol. The
resulting borate esters and excess solvent were removed by
rotary evaporation. The remaining aqueous solution was
basified to pH 13–14 and extracted with dichloromethane
(5£50 mL). The organic layers were combined, dried with
Na2SO4 and concentrated to give 5a as a clear oil (3.24 g,
96% yield); IR: nmax (Golden Gate) 1136, 1165, 1215, 1252,
1323, 1458, 1560, 2341, 2360 and 2943 cm21; 1H NMR: dH
(CDCl3) 0.06 (9H, s), 0.98–1.04 (2H, m), 1.42–1.49 (4H,
m), 1.60–1.68 (4H, m), 2.71–2.73 (4H, t, J¼7.0 Hz), 3.20–
3.24 (4H, t, J¼7.7 Hz); 13C NMR: dC (CDCl3) 21.6, 10.7,
26.9, 31.1, 42.1, 48.4, 48.9; MS: m/z (FABþ mode) 324.2
([MþH]þ, 50%), 253.1 (10), 226.1 (5), 136.1 (6), 101.4 (5),
73.8 (100) and 70.9 (23). Found [MþH]þ 324.2147,
C13H34O2N3SiS requires 324.2141.
1
1547, 2900 and 2952 cm21; H NMR: dH (CDCl3) 0.07
(9H, s), 1.06–1.10 (2H, m), 3.03–3.07 (2H, m), 4.82 (2H,
s); 13C NMR: dC (CDCl3) 21.6, 11.2, 51.9; MS: m/z (CIþ
mode) 182.12 ([MþH]þ, 5%), 166.09 (100), 154.09 (7),
138.06 (11), 122.12 (5), 101.14 (10), 85.14 (11), 71.09 (10).
Found [MþH]þ 182.0669, C5H16O2NSiS requires
182.0671.
4.2. Typical procedure for the synthesis of 4a-c
4.2.1. N-(2-(Trimethylsilyl)ethanesulfonyl)-bis-(3-cyano-
propyl)amine (4a). Compound 3 (2.00 g, 11.0 mmol),
dissolved in DMF (30 mL) with caesium carbonate
(33.0 mmol), was treated with 4-bromobutyronitrile
(3.27 g, 22.1 mmol) and stirred at room temperature for
24 h. The DMF was removed by rotary evaporation under
high vacuum and the residue taken up in dichloromethane
(50 mL), which was washed with water (50 mL) and brine
(50 mL), dried with Na2SO4 and evaporated to give the
crude substituted sulfonamide (no purification necessary) as
a beige oil (3.35 g, 96% yield); IR: nmax (Golden Gate)
1138, 1167, 1250, 1327, 1421, 1460, 1672, 2247 and
4.3.2. 7-(2-(Trimethylsilyl)ethanesulfonyl)-1,7,13-tri-
azatridecane (5b). Using 4b (2.10 g, 6.11 mmol), 5b was
prepared as a clear oil (2.05 g, 95% yield); IR: nmax (Golden
Gate) 1167, 1248, 1327, 1560, 2862 and 2927 cm21; H
NMR: dH (CDCl3) 0.06 (9H, s), 0.98–1.02 (2H, m), 1.24–
1.51 (12H, m), 1.56–1.64 (4H, quintet, J¼7.1 Hz), 2.68–
2.72 (4H, t, J¼7.1 Hz), 2.83–2.88 (2H, m), 3.18–3.22 (4H,
t, J¼7.6 Hz); 13C NMR: dC (CDCl3) 21.7, 10.7, 24.3, 29.3,
33.6, 42.3, 48.1, 48.3; MS: m/z (FABþ mode) 352.5
([MþH]þ 100%), 226.2 (7), 169.2 (3), 84.6 (24), 73.7 (95).
Found [MþH]þ 352.2452, C15H38O2N3SiS requires
352.2454.
1
2953 cm21; H NMR: dH (CDCl3) 0.07 (9H, s), 0.98–1.04
1
(2H, m), 1.95–2.03 (4H, quintet, J¼7.1 Hz), 2.44–2.48
(4H, t, J¼7.1 Hz), 2.84–2.96 (2H, m), 3.32–3.36 (4H, t,
J¼7.1 Hz); 13C NMR: dC (CDCl3) 21.6, 11.6, 15.0, 47.9,
48.4, 119.2; MS: m/z (FABþ mode) 338.1 ([MþNa]þ,
100%), 271.1 (10), 73.8 (30). Found [MþNa]þ 338.1335,
C13H25O2N3SiSNa requires 338.1334.
4.2.2. N-(2-(Trimethylsilyl)ethanesulfonyl)-bis-(4-cyano-
butyl) amine (4b). Using 5-bromovaleronitrile (2.68 g,
16.54 mmol) and 3 (1.5 g, 8.27 mmol), 4b was prepared as
above and purified by column chromatography (EtOAc,
silica) to give a yellow oil (2.16 g, 76% yield); Rf
(EtOAc)¼0.64; IR: nmax (Golden Gate) 1140, 1167, 1250,
1329, 2249 and 2952 cm21; 1H NMR: dH (CDCl3) 0.06 (9H,
s), 0.97–1.01 (2H, m), 1.68–1.81 (8H, m), 2.42–2.45 (4H,
t, J¼6.6 Hz), 2.85–2.90 (2H, m), 3.24–3.28 (4H, t,
J¼6.8 Hz); 13C NMR: dC (CDCl3) 21.6, 10.7, 17.1, 22.6,
47.8, 48.0, 119.6; MS: m/z (CIþ mode) 344.3 ([MþH]þ,
35%), 316.2 (9), 280.3 (2), 252.2 (30), 226.2 (4), 211.2
(3), 180.2 (2), 138.2 (1), 111.1 (1), 73.1 (3), 57.1 (100).
Found [MþH]þ 344.1827, C15H30O2N3SiS requires
344.1828.
4.3.3. 8-(2-(Trimethylsilyl)ethanesulfonyl)-1,8,15-triaza-
pentadecane (5c). Using 4c (2.24 g, 6.03 mmol), 5c was
prepared as a clear oil (2.22 g, 97% yield); IR: nmax (Golden
Gate) 1165, 1250, 1325, 1464, 1572, 2856 and 2929 cm21
1H NMR: dH (CDCl3) 0.04 (9H, s), 0.97–1.01 (2H, m),
1.21–1.48 (16H, m), 1.54–1.61 (4H, quintet, J¼7.2 Hz),
2.68 (4H, t, J¼7.2 Hz), 2.82–2.86 (2H, m), 3.18 (4H, t,
J¼6.7 Hz); 13C NMR: dC (CDCl3) 21.6, 10.7, 26.9, 26.9,
29.4, 33.9, 42.3, 48.1, 48.3; MS: m/z (FABþ mode) 380.5
([MþH]þ 72%), 288.4 (3), 226.2 (4), 185.3 (4), 98.5 (16),
73.7 (100). Found [MþH]þ 380.2773, C17H42O2N3SiS
requires 380.2767.
;
4.2.3. N-(2-(Trimethylsilyl)ethanesulfonyl)-bis-(cyano-
pentyl)amine (4c). Using 6-bromocapronitrile (2.91 g,
16.54 mmol) and 3 (1.5 g, 8.27 mmol), 4c was purified by
column chromatography (EtOAc, silica) to give a yellow oil
(2.26 g, 73% yield); Rf (EtOAc)¼0.61; IR: nmax (Golden
4.4. Typical procedure for the synthesis of 6a-c
4.4.1. 1,6,11-Triazaundecane (6a). Compound 5a (3.24 g,
10.0 mmol) was dissolved in dry DMF (100 mL) and the
solution was added via syringe to a flask with caesium
fluoride (10 equiv., previously dried under vacuum for 3 h at
,2008C). The suspension was heated to 1008C overnight
Gate) 1139, 1250, 1327 and 2951 cm21 1H NMR: dH
;
(CDCl3) 0.06 (9H, s), 0.97–1.02 (2H, m), 1.45–1.53 (4H,
m), 1.61–1.74 (8H, m), 2.35–2.39 (4H, t, J¼7.0 Hz), 2.84–
2.88 (2H, m), 3.19–3.22 (4H, t, J¼7.5 Hz); 13C NMR: dC
(CDCl3) 21.6, 10.7, 17.5, 25.3, 26.1, 29.0, 48.2, 48.3,
119.85; MS: m/z (FABþ mode) 372.4 ([MþH]þ, 12%),
280.4 (92), 226.2 (12), 197.2 (12), 149.1 (28), 73.7 (100),
56.0 (9). Found [MþH]þ 372.2153, C17H34O2N3SiS
requires 372.2141.
1
while stirring, checking evaporated aliquots by H NMR
spectroscopy for disappearance of SES peaks. Upon
completion (48 h), MeOH was added (2–5 mL) and the
solvent was removed by rotary evaporation under high
vacuum. The residue was taken up in dichloromethane,
filtered through a small pad of Celite, and the solution
1
evaporated to give 6a as a beige oil (1.34 g, 84%); H and

L. L. Parker et al. / Tetrahedron 59 (2003) 10165–10171
10169
13C NMR spectra agreed with literature values.14 1H NMR:
dH (CDCl3) 1.39–1.52 (8H, m), 2.57 (4H, t, J¼6.9 Hz), 2.66
(4H, t, J¼6.7 Hz); 13C NMR: dC (CDCl3) 27.8, 31.8, 42.4,
50.1.
(1.33 g, 52% yield); mp¼145.5–146.88C; IR: nmax (Golden
Gate) 1036, 1072, 1109, 1130, 1171, 1244, 1267, 1284,
1
1311, 1421, 2954 and 3278 cm21; H NMR: dH (CDCl3)
0.07 (27H, s), 0.98–1.03 (6H, m), 1.60–1.67 (4H, m),
1.74–1.80 (4H, m), 2.86–2.97 (6H, m), 3.14–3.20 (4H, q,
J¼6.2 Hz), 3.23–3.27 (4H, t, J¼7.2 Hz), 4.93–4.96 (2H, t,
J¼6.2 Hz); 13C NMR: dC (CDCl3) 21.6, 10.5, 10.9, 26.5,
27.6, 43.0, 47.6, 48.7, 49.2; MS: m/z (FABþ mode NaI)
674.1 ([MþNa]þ, 56%), 560.2 (13), 486.1 (10), 305.1 (22),
136.0 (9), 73.3 (100). Found [MþNa]þ 674.2609, C23H57-
O6N3Si3S3Na requires 674.2615.
4.4.2. 1,7,13-Triazatridecane (6b). Using 5b (0.200 g,
0.569 mmol), 6b was prepared to give an oil (0.089 g, 84%
1
yield); H and 13C NMR agreed with literature values.5 1
H
NMR: dH (CDCl3) 1.34–1.61 (10H, m), 2.62 (4H, t,
J¼7.2 Hz), 2.71 (4H, t, J¼6.9 Hz); 13C NMR: dC (CDCl3)
25.1, 30.4, 34.1, 42.5, 50.4.
4.4.3. 1,8,15-Triazapentadecane (6c). Using 5c (1.45 g,
3.82 mmol), 6c was prepared to give an oil (0.38 g, 46%
4.5.4. 1,7,13-Tris-2(trimethylsilyl)ethanesulfonyl-1,7,13-
triazatridecane (7d). Using 5b (2.00 g, 5.69 mmol) and 2
(2.86 g, 14.2 mmol), 7d was recrystallised from isopropa-
nol/water (,2:1) to give a cream solid (2.42 g, 62% yield);
mp¼95–998C; IR: nmax (Golden Gate) 1171, 1246, 1315
yield); 1H and 13C NMR agreed with literature values.15 1
H
NMR: dH (CDCl3) 1.33–1.55 (12H, m), 2.60 (4H, t,
J¼7.2 Hz), 2.69 (4H, t, J¼6.9 Hz); 13C NMR: dC (CDCl3)
27.2, 27.7, 30.6, 34.2, 42.5, 50.4.
1
and 2951 cm21; H NMR: dH (CDCl3) 0.05 (9H, s), 0.06
(18H, s), 0.97–1.03 (6H, m), 1.39–1.45 (4H, m), 1.57–1.67
(8H, m), 2.84–2.88 (2H, m), 2.91–2.95 (4H, m), 3.12 (4H,
q, J¼6.3 Hz), 3.20 (4H, t, J¼7.4 Hz), 4.49 (2H, t,
J¼6.3 Hz); 13C NMR: dC (CDCl3) 21.6, 10.7, 11.0, 23.8,
29.0, 30.3, 43.4, 48.0, 48.4, 49.0, 138.4; MS: m/z (FABþ
mode NaI) 702.6 ([MþNa]þ 38%), 664.5 (5), 616.6 (6),
588.6 (18), 516.5 (22), 514.5 (18), 333.4 (18), 279.3 (9),
215.2 (8), 136.1 (20), 73.4 (99). Found [MþNa]þ 702.2898,
C25H61N3O6Si3S3Na requires 702.2928.
4.5. Typical procedure for the synthesis of 7a-e
4.5.1. 1,5,9-Tris-2(trimethylsilyl)ethanesulfonyl-1,5,9-
triazanonane (7a). Dipropylenetriamine
(0.820 g,
6.23 mmol) was dissolved in dry DMF (12 mL) in an
oven-dried, N2-cooled 3-neck round-bottom flask with stir
bar, pressure-equalising dropping funnel and internal
thermometer. Triethylamine (5 equiv.) was added and the
mixture was cooled to 08C in an immersion-cooler cold
bath. Neat SES-Cl (4 equiv.) was added dropwise, suffi-
ciently slowly to keep the internal temperature below 108C
(in order to minimise decomposition of the sulfonyl chloride
in the presence of triethylamine). The mixture was stirred
overnight while being held at 08C, then the DMF was
removed by rotary evaporation under high vacuum. The
residue was taken up in water (50 mL) and dichloromethane
(50 mL). The organic layer was washed with brine (25 mL),
dried with Na2SO4 and concentrated to give 7a, which was
purified by column chromatography (9:1 DCM/EtOAc,
silica) to give a cream solid (2.77 g, 71.1% yield);
mp¼100.2–101.58C (lit. 106.5–107.58C8); NMR and IR
data agreed with literature values.8
4.5.5. 1,8,15-Tris-2(trimethylsilyl)ethanesulfonyl-1,8,15-
triazapentadecane (7e). Using 5c (2.20 g, 5.79 mmol) and
2 (3.02 g, 15.0 mmol), 7e was purified by column
chromatography to give white crystals (2.67 g, 65%);
mp¼89–918C; IR: nmax (Golden Gate) 1173, 1246, 1284,
1
1313, 1460, 2856 and 2929 cm21; H NMR: dH (CDCl3)
0.05 (9H, s), 0.06 (18H, s), 0.97–1.03 (6H, m), 1.35–1.44
(8H, m), 1.54–1.63 (8H, m), 2.83–2.88 (2H, m), 2.91–2.95
(4H, m), 3.11 (4H, q, J¼6.4 Hz), 3.19 (4H, t, J¼7.5 Hz),
4.50 (2H, t, J¼6.4 Hz); 13C NMR: dC (CDCl3) 21.6, 1.4,
10.7, 11.0, 26.3, 29.3, 30.7, 43.5, 48.1, 48.3, 49.0; MS: m/z
(FABþ mode NaI) 730.7 ([MþNa]þ 12%), 616.7 (4), 542.5
(3), 293.3 (1), 226.2 (1), 147.1 (2), 73.3 (100), 44.1 (12).
Found [MþNa]þ 730.3224, C27H65N3O6Si3S3Na requires
730.3241.
4.5.2. 1,5,10-Tris-2(trimethylsilyl)ethanesulfonyl-1,5,10-
triazadecane (7b). Using spermidine (2.60 g, 36.1 mmol),
7b was prepared and purified by recrystallisation from
MeOH/H2O (1:1) to give a cream powder (10.0 g, 87%
yield); mp¼104–1068C; IR: nmax (CDCl3 solution cell)
1142, 1169, 1254, 1327, 1383, 1468, 2900, 2956, 3294 and
3394 cm21; 1H NMR: dH (CDCl3) 0.06 (27H, s), 0.98–1.04
(6H, m), 1.57–1.64 (2H, quintet, J¼6.8 Hz), 1.69–1.76
(2H, quintet, J¼6.8 Hz), 1.82–1.88 (2H, quintet,
J¼6.0 Hz), 2.87–2.96 (6H, m), 3.12–3.37 (8H, m), 4.64
(1H, t, J¼6.8 Hz), and 5.17 (1H, t, J¼6.8 Hz); 13C NMR: dC
(CDCl3) 21.60, 10.9, 26.5, 27.7, 30.6, 40.3, 43.0, 46.1,
47.7, 49.0; MS: m/z (FABþ mode NaI) 660.1 ([MþNa]þ,
100%), 494.2 (11.5), 330.2 (6.5), 273.1 (7), 147.1 (5), 73.8
(98), and 60.0 (8). Found [MþNa]þ 660.2457, C22H55O6-
N3Si3S3Na requires 660.2459.
4.6. Typical procedure for synthesis of 9a-f
4.6.1. 1,5,9-Tris-(2-(trimethylsilyl)ethanesulfonyl)-1,5,9-
triazacyclotetradecane [3,3,5] (9a). Compound 7a (2.00 g,
3.20 mmol) and caesium carbonate (3 equiv.) were com-
bined in wet DMF (30 mL). 8b11 (1.32 g, 3.20 mmol) in wet
DMF (10 mL), was dripped in slowly via pressure-
equalising dropping funnel. The mixture was stirred
vigorously for 3–7 days, checking daily for disappearance
of ditosylate by TLC of an evaporated aliquot. Upon
completion (6 days), the DMF was removed by rotary
evaporation under high vacuum and the residue taken up in
dichloromethane (100 mL) which was washed with water
and brine (50 mL each), dried with Na2SO4, and concen-
trated to give crude 9a, which was purified by column
chromatography (20:1 DCM/EtOAc, silica) to give a white
solid (1.21 g, 54% yield); mp¼175.0–177.38C; IR: nmax
(CDCl3 solution cell) 1142, 1167, 1254, 1333, 1381, 1464,
4.5.3. 1,6,11-Tris-2(trimethylsilyl)ethanesulfonyl-1,6,11-
triazaundecane (7c). Using 5a (1.27 g, 3.97 mmol) in DMF
(10 mL) and 2 (2.00 g, 9.94 mmol), 7c was prepared and
purified by column chromatography to give a white solid
1
2866, 2902 and 2956 cm21; H NMR: dH (CDCl3) 0.06

10170
L. L. Parker et al. / Tetrahedron 59 (2003) 10165–10171
(27H, s), 0.96–1.04 (6H, m), 1.57–1.64 (2H, m), 1.67–1.72
(4H, m), 1.90–1.97 (4H, m), 2.84–2.89 (6H, m), 3.23–3.40
(12H, m); 13C NMR: dC (CDCl3) 21.6, 10.4, 10.6, 23.7,
29.4, 31.0, 45.8, 46.9, 48.5, 48.7, 50.7; MS: m/z (FABþ
mode NaI) 714.1 ([MþNa]þ, 15%), 548.2 (4), 526.2 (4),
362.2 (3), 360.2 (2.9), 268.2 (1), 210.1 (5), 98.5 (5) and 73.8
(100). Found [MþNa]þ 714.2930, C26H61O6N3Si3S3Na
requires 714.2928.
Gate) 1136, 1165, 1250, 1327 and 2951 cm21; 1H NMR: dH
(CDCl3) 0.05 (27H, s), 0.97–1.02 (6H, m), 1.40–1.47 (4H,
m), 1.59–1.69 (12H, m), 2.84–2.88 (6H, m), 3.18–3.24
(12H, m); 13C NMR: dC (CDCl3) 21.6, 1.4, 10.6, 10.7, 23.6,
27.6, 29.4, 30.1, 47.3, 47.7, 48.6, 49.6, 49.7; MS: m/z
(FABþ mode) 734.8 ([MþH]þ 2%), 718.7 (2), 670.8 (4),
614.7 (4), 568.6 (6), 404.5 (6), 402.5 (4), 210.2 (6), 147.1
(3), 73.7 (100). Found [MþH]þ 734.3541, C29H68O6N3Si3-
S3 requires 734.3578.
4.6.2. 1,5,10-Tris-(2-trimethylsilyl)ethanesulfonyl)-
1,5,10-triazacyclotetradecane [4,4,3] (9b). Using 7b
(2.00 g, 3.13 mmol) and 8a11 (1.25 g, 3.13 mmol) in DMF
(40 mL), 9b was purified by column chromatography to
give a white solid (0.90 g, 41%); mp¼145.0–147.68C; IR:
nmax (CDCl3 solution cell) 1142, 1167, 1254, 1333, 1379,
4.6.6. 1,6,13-Tris-(2-trimethylsilanyl-ethanesulfonyl)-
1,6,13-triaza-cyclononadecane [6,6,4] (9f). Using 7e
(2.60 g, 3.66 mmol) and 8a (1.34 g, 3.66 mmol), 9f was
purified by column chromatography to give a white solid
(0.59 g, 21% yield); mp¼129–1348C; IR: nmax (Golden
Gate) 1167, 1248, 1327, 2860 and 2929 cm21; 1H NMR: dH
(CDCl3) 0.05 (27H, s), 0.97–1.01 (6H, m), 1.37–1.44 (8H,
m), 1.62–1.68 (12H, m), 2.83–2.88 (6H, m), 3.16–3.23
(12H, m); 13C NMR: dC (CDCl3) 21.6, 1.3, 10.5, 26.3, 26.3,
27.1, 29.7, 29.9, 46.7, 46.9, 49.3, 49.9, 50.0; MS: m/z
(FABþ mode) 762.8 ([MþH]þ 2%), 746.8 (3), 698.8 (7),
642.7 (6), 596.7 (17), 432.6 (13), 430.6 (11), 210.2 (6),
147.1 (3) 73.7 (100). Found [MþH]þ 762.3885, C15H30O2-
N3SiS requires 762.3891.
1
1460, 2866, 2922 and 2956 cm21; H NMR: dH (CDCl3)
0.05 (27H, s), 0.97–1.03 (6H, m), 1.76 (8H, bs), 1.99–2.05
(2H, m), 2.83–2.88 (6H, m), 3.20–3.30 (12H, m); 13C
NMR: dC (CDCl3) 21.6, 10.37, 10.42, 27.5, 27.6, 32.8,
45.9, 49.0, 50.4, 51.6; MS: m/z (FABþ mode NaI) 714.1
([MþNa]þ, 27%), 548.2 (6), 362.2 (5), 360.2 (4), 305.2 (1),
210.1 (5), 142.1 (2), 84.5 (10), 73.8 (100), and 59.9 (5).
Found [MþNa]þ 714.2926, C26H61O6N3Si3S3Na requires
714.2928.
4.6.3. 1,5,10-Tris-(2-(trimethylsilyl)ethanesulfonyl)-
1,5,10-triazacyclopentadecane [3,4,5] (9c). Using 7b
(5.00 g, 7.82 mmol) and 8b (3.23 g, 7.82 mmol), 9c was
purified by column chromatography to give a white glassy
solid (2.41 g, 47% yield); mp¼95.2–97.58C; IR: nmax
(CDCl3 solution cell) 1140, 1167, 1254, 1333, 1377,
4.7. Typical procedure for synthesis of 10a-f
4.7.1. 1,5,9-Triazacyclotetradecane [3,3,5] (10a). Using
9a (1.21 g, 1.75 mmol), 10a was prepared according to the
typical procedure for 6a-c and purified by Kugelrohr
distillation (0.035 mm Hg/1718C) to give a clear oil
(0.216 g, 62% yield); 1H NMR: dH (CDCl3) 1.43–1.57
(8H, m), 1.67–1.73 (2H, m), 2.65–2.73 (12H, m); 13C
NMR: dC (CDCl3) 20.9, 25.7, 28.5, 47.2, 47.5, 49.2; MS:
m/z (EIþ mode) 199.2 ([Mz]þ, 18%), 198.2 (3), 170.2 (2),
155.1 (5), 141.1 (6), 112.11 (15), 98.1 (48), 82.9 (100), 70.1
(28) and 47.0 (30). Found [Mz]þ 199.2049, C11H25N3
requires 199.2048.
1
1464, 2868, 2902 and 2956 cm21; H NMR: dH (CDCl3)
0.06 (27H, s), 0.96–1.03 (6H, m), 1.55–1.65 (10H, m),
1.94–1.98 (2H, m), 2.84–2.89 (6H, m), 3.20–3.34 (12H,
m); 13C NMR: dC (CDCl3) 21.67, 21.63, 21.59, 10.4,
10.5, 10.6, 23.6, 27.1, 27.6, 28.6, 28.7, 31.5, 46.0, 46.7,
47.2, 47.3, 47.4, 48.6, 49.3, 49.4, 49.5 and 50.9; MS: m/z
(FABþ mode NaI) 728.1 ([MþNa]þ, 93%), 654.1 (1.5),
562.2 (17), 540.2 (4), 490.2 (1), 420.2 (1), 398.2 (11), 376.2
(2.5), 341.2 (1), 210.1 (5), 177.2 (1.5), 84.7 (6.5) and 73.8
(100). Found [MþNa]þ 728.3083, C27H63O6N3Si3S3Na
requires 728.3085.
4.7.2. 1,5,10-Triazacyclotetradecane [3,4,4] (10b). Using
9b (0.897 g, 1.28 mmol), 10b was prepared and purified by
Kugelrohr distillation (0.1 mm Hg/1708C) to give a pale
yellow oil (0.084 g, 33%); 1H NMR: dH (CDCl3) 1.55–1.64
(8H, m), 1.68–1.74 (2H, m), 2.64–2.74 (12H, m); 13C
NMR: dC (CDCl3) 25.2, 25.9, 46.2, 48.2, 49.1; MS: m/z
(EIþ mode) 199.2 ([Mz]þ, 19%), 182.2 (3), 154.1 (5), 141.1
(7), 112.1 (15), 98.1 (26), 84.0 (100), 63.0 (51) and 44.1
(23). Found [Mz]þ 199.2047, C11H25N3 requires 199.2048.
4.6.4. 1,6,11-Tris-(2-(trimethylsilyl)ethanesulfonyl)-
1,6,11-triazacyclopentadecane [4,4,4] (9d). Using 7c
(0.940 g, 1.45 mmol) and 8a (0.580 g, 1.45 mmol), 9d was
purified by column chromatography to give a white solid
(0.294 g, 29% yield); mp¼133.2–135.08C; IR: nmax
(Golden Gate) 1045, 1105, 1134, 1167, 1211, 1248, 1325,
1376, 1417, 1456, 2952 and 3020 cm21
;
1H NMR: dH
4.7.3. 1,5,10-Triazacyclopentadecane [3,4,5] (10c). Using
9c (1.27 g, 1.80 mmol), 10c was prepared and purified by
Kugelrohr distillation (0.1 mm Hg/1708C) to give a pale
yellow oil (0.150 g, 39%); 1H NMR: dH (CDCl3) 1.49–1.60
(10H, m), 1.64–1.70 (2H, m), 2.61–2.74 (12H, m); 13C
NMR: dC (CDCl3) 23.9, 27.2, 27.9, 28.1, 28.6, 28.8, 47.9,
48.3, 48.6, 49.7, 50.2; MS: m/z (EIþ mode) 213.2 ([Mz]þ,
19%), 196.2 (3), 183.2 (3), 155.2 (6), 141.1 (6), 126.1 (13),
98.1 (53), 84.0 (100), 82.9 (48), 70.1 (36) and 47.0 (34).
Found [Mz]þ 213.2206, C12H27N3 requires 213.2205.
(CDCl3) 20.07 (27H, s), 0.80–0.93 (6H, m), 1.58 (12H,
broad s), 2.66–2.81 (6H, m), 3.11 (12H, broad s); 13C NMR:
dC (CDCl3) 21.59, 10.5, 27.3, 46.2, 50.1; MS: m/z (FABþ
mode NaI) 728.3 ([MþNa]þ, 70%), 690.2 (13), 642.3 (15),
540.3 (60), 476.3 (6), 376.2 (42), 374.2 (27), 210.0 (31),
142.1 (10). Found [MþNa]þ 728.3054, C27H63O6N3Si3S3-
Na requires 728.3084.
4.6.5. 1,6,12-Tris-(2-(trimethylsilyl)ethanesulfonyl)-
1,6,12-triaza-cycloheptadecane [5,5,4] (9e). Using 7d
(1.80 g, 2.64 mmol) and 8a (0.97 g, 2.64 mmol), 9e was
purified by column chromatography to give a white solid
(0.56 g, 29% yield); mp¼120–1248C; IR: nmax (Golden
4.7.4. 1,6,10-Triazacyclopentadecane [4,4,4] (10d). Using
9d (0.294 g, 0.416 mmol), 10d was prepared and purified by
Kugelrohr distillation (0.05 mm Hg/1608C) to give a pale

L. L. Parker et al. / Tetrahedron 59 (2003) 10165–10171
10171
1
tan oil (0.060 g, 67% yield); H NMR: dH (CDCl3) 1.59
(12H, broad s), 2.68 (12H, broad s); 13C NMR: dC (CDCl3)
27.3, 48.7; MS: m/z (FABþ mode) 214.2 ([MþH]þ, 100%),
212.2 (11), 126.1 (12), 84.6 (7), 73.7 (10), 48.0 (6). Found
[MþH]þ 214.2285, C12H28N3 requires 214.2283.
References
1. Cowan, J. A. Curr. Opin. Chem. Biol. 2001, 5, 634.
2. Jeon, J. W.; Son, S. J.; Yoo, C. E.; Hong, I. S.; Song, J. B.; Suh,
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3. Alexander, V. Chem. Rev. 1995, 95, 273.
4.7.5. 1,6,12-Triazacycloheptadecane [5,5,4] (10e). Using
9e (0.50 g, 0.681 mmol), 10e was prepared and purified by
Kugelrohr distillation (0.05 mm Hg/1508C) to give a clear
4. Gladkikh, O. P.; Inwood, H.; Nicholls, D.; Weatherburn, D. C.
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1
oil (0.054 g, 33% yield); H NMR: dH (CDCl3) 1.35–1.59
(19H, m), 2.62–2.66 (12H, m); 13C NMR: dC (CDCl3) 24.7,
27.7, 29.1, 29.3, 48.7, 49.0, 49.1; MS: m/z (EIþ mode)
241.3 ([MþH]þ, 14%), 225.3 (2), 200.3 (3), 183.2 (4), 155.2
(11), 140.2 (22), 112.2 (21), 84.1 (100), 70.1 (34), 44.1 (23).
Found [MþH]þ 241.2520, C14H31N3 requires 241.2518.
6. Webb, H. K.; Wu, Z.; Sirisoma, N.; Ha, H. C.; Casero, R. A.,
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J. S., Krakowiak, K. E., Izatt, R. M., Eds.; Wiley: New York,
1993.
4.7.6. 1,6,13-Triazacyclononadecane [6,6,4] (10f). Using
9f (0.49 g, 0.643 mmol), 10f was prepared and purified by
Kugelrohr distillation (0.05 mm Hg/1658C) to give a clear
1
oil (0.054 g, 31% yield); H NMR: dH (CDCl3) 1.38–1.58
10. Chavez, F.; Sherry, A. D. J. Org. Chem. 1989, 54, 2990.
11. Searle, G. H.; Geue, R. J. Aust. J. Chem. 1984, 37, 959.
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13. Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. Org.
Synth. 1997, 75, 161.
(23H, m), 2.62–2.68 (12H, m); 13C NMR: dC (CDCl3) 26.5,
26.7, 27.7, 29.4, 29.6, 28.7, 49.0, 49.4; MS: m/z (EIþ mode)
269.4 ([MþH]þ, 43%), 237.3 (5), 225.3 (6), 211.3 (14),
169.2 (25), 154.2 (23), 126.2 (33), 112.2 (97), 84.1 (100),
70.1 (57), 55.1 (44). Found [MþH]þ 269.2833, C16H35N3
requires 241.2518.
14. Bergeron, R. J.; Burton, P. S.; McGovern, K. A.; Kline, S. J.
Synthesis 1981, 9, 732.
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16. Byproduct from polymer composition intermediate synthesis,
commercially available.
Acknowledgements
17. Ida, K.; Okawa, H.; Sakiyama, H.; Kodera, M.; Kida, S.;
Murase, I. Inorg. Chim. Acta 1991, 184, 197.
We thank the University of Glasgow for a University 2001
Scholarship and Universities UK for an ORS award (LLP).
We also thank Dr Rebecca Hoye of Macalester College,
MN, USA for her advice on the cyclisation of SES-amides.
18. Crown Ethers and Cryptands; Gokel, G., Ed.; The Royal
Society of Chemistry: Cambridge, UK, 1991.
19. Burfield, D. R.; Smithers, R. H. J. Org. Chem. 1978, 43, 3966.