Investigation of macrocyclisation routes to 1,4,7-triazacyclononanes: Efficient syntheses from 1,2-ditosylamides

Article abstract of DOI:10.1039/b716938h

Two routes to the synthesis of a cyclohexyl-fused 1,4,7-triazacyclononane involving macrocyclisations of tosamides have been investigated. In the first approach, using a classic Richman-Atkins-type cyclisation of a cyclohexyl-substituted 1,4,7-tritosamide

Full text of DOI:10.1039/b716938h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Investigation of macrocyclisation routes to 1,4,7-triazacyclononanes: efficient
syntheses from 1,2-ditosylamides†
Graham Stones, Re´gis Tripoli, Colin L. McDavid, Kewin Roux-Duplaˆtre, Alan R. Kennedy,
David C. Sherrington and Colin L. Gibson*‡
Received 1st November 2007, Accepted 20th November 2007
First published as an Advance Article on the web 11th December 2007
DOI: 10.1039/b716938h
Two routes to the synthesis of a cyclohexyl-fused 1,4,7-triazacyclononane involving macrocyclisations
of tosamides have been investigated. In the first approach, using a classic Richman–Atkins-type
cyclisation of a cyclohexyl-substituted 1,4,7-tritosamide with ethylene glycol ditosylate, afforded the
cyclohexyl-fused 1,4,7-triazacyclononane in 5.86% overall yield in four steps. The second, more concise,
approach involving the macrocyclisation of trans-cyclohexane-1,2-ditosamide with the tritosyl
derivative of diethanolamine initially gave poor yields (< 25%). The well-documented problems with
efficiencies in macrocyclisations using 1,2-ditosamides led to the use of a wider range of 1,2-ditosamides
including ethane-1,2-ditosamide and propane-1,2-ditosamide. These extended studies led to the
development of an efficient macrocyclisation protocol using lithium hydride. This new method afforded
1,4,7-tritosyl-1,4,7-triazacyclononanes in good yield (57–90%) from 1,2-ditosamides in a single step.
These efficient methods were then applied to the preparation of a chiral cyclohexyl-fused
1,4,7-tritosyl-1,4,7-triazacyclononane (65–70%). This key chiral intermediate was then converted into a
copper(II) complex following detosylation and N-methylation. The resulting chiral copper(II) complex
catalysed the aziridination of styrene but it did so in a racemic fashion.
peptides.16 Intriguingly, the copper(II) trifluoroacetate complex
of 1,4,7-triisopropyl-1,4,7-triazacyclononane was reported by
Introduction
Polyazamacrocycles continue to stimulate considerable interest
Halfen et al. to be a remarkably efficient catalyst for the achiral
aziridination of alkenes.17
because of their varied coordination chemistry coupled with
their biological properties and the synthetic utility of the derived
metal ion complexes.1 More specifically, the tridentate 1,4,7-
triazacyclononanes are of particular interest because of their
ability to stabilise both high and low oxidation states of various
metal ions.2 In this context, transition metal complexes of 1,4,7-
triazacyclononane derivatives have been studied as biomimetics
of manganese catalase,3,4 Photosystem II3,5 and hemocyanin.6
These biological model systems studies led to the development
of manganese complexes of 1,4,7-triazacyclononane derivatives
as potent alkene epoxidation catalysts.7 Indeed, stereoselective
alkene epoxidation protocols have been developed while enantios-
elective epoxidations using manganese complexes of chiral 1,4,7-
triazacyclononane derivatives have been described by Beller et al.,8
Bolm et al.9,10 and ourselves.11 Manganese complexes of derivatives
of 1,4,7-triazacyclononane have also been used in the oxidation
of sulfides, alcohols and alkanes.7 Recently, an iron(III) complex
of 1,4,7-trimethyl-1,4,7-triazacyclononane was found to catalyse
the atom transfer radical polymerisation of styrene.12 In addition,
hydrolytic catalysts have been developed from copper(II), zinc(II)
and iron(III) complexes of derivatives of 1,4,7-triazacyclononane
which have been used in the cleavage of RNA,13 DNA14,15 and
Given the foregoing interest in 1,4,7-triazacyclononanes it
is not surprising that chiral analogues have been prepared,
including those with one,11b,18 two [(C-2,3),19 (C-2,5)20 and (C-
2,6)11a,21,22] and three10 stereocentres on the carbon backbone of the
macrocyclic ring. Despite this significant synthetic interest, the use
of complexes of metal ions and chiral 1,4,7-triazacyclononanes,
generated in situ or isolated entities, have been limited to
enantioselective epoxidations.8–11 However, a copper(II) complex
of a chiral 4-oxa-1,7-diazonane has been used as a catalyst in
the racemic hetero-Diels–Alder cycloaddition.19c Therefore, we
were interested in trying to extend the catalytic repertoire of
chiral 1,4,7-trizacyclononane-metal ion complexes in asymmetric
transformations. We were particularly excited by the achiral alkene
aziridination of Halfen et al. using copper(II) 1,4,7-triisopropyl-
1,4,7-triazacyclononane (vide supra)17 and wished to investigate
chiral variants. Furthermore, we were keen to extend our investi-
gations in asymmetric epoxidation studies using chiral manganese
complexes.11,23 Since high enantiomeric excess had been claimed
Department of Pure & Applied Chemistry, University of Strathclyde, 295
Cathedral Street, Glasgow, UK G1 1XL. E-mail: c.l.gibson@strath.ac.uk
† Electronic supplementary information (ESI) available: Instrumentation,
general synthetic methods and full experimental procedures for the
synthesis via Route B, including compounds; ( )-3, ( )-6 ( )-10, 12,
(
)-13. See DOI: 10.1039/b716938h
‡ Based on G. Stones, Ph.D. Thesis, University of Strathclyde, 2003.
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for alkene epoxidations using manganese complexes of cyclohexyl-
fused azamacrocycle 1,8 we wished to prepare and investigate
complexes of this conformationally constrained system.
developing efficient routes to tritosamide 3 we then planned to
prepare the N-methyl derivative 1 and then prepare manganese
and copper(II) complexes. These complexes were to be studied in
catalytic asymmetric alkene epoxidations and aziridinations.
In order to develop efficient routes to the tritosamide 3 it was
important to address the issues of the cyclisation chemistry. In view
of the observations of Searle and Geue (vide supra) we envisiged
an alternative disconnection of tritosamide 3 (Scheme 1, Route B).
This route involved the classic Richman–Atkins cyclisation of the
1,4,7-tritosamide 6 with ethylene glycol ditosylate 7. Since both
Route A and Route B proceed via common intermediate 8, then
these studies may lead to an understanding of the moderate yields
obtained in Route A (Scheme 1).
The cyclohexyl-fused azamacrocycle 1 was prepared by Beller
et al. from the corresponding non-methylated derivative 2, which,
in-turn, was accessed from the tritosamide 3.19a At the outset of
our work, Beller et al. had reported the preparation of cyclohexyl-
fused tritosamide 3 by the macrocyclisation of the disodium
salt of cyclohexyl ditosamide 4 with tosyl ester 5 in 68% yield
(Scheme 1, Route A).19a In contrast, Lawrence and co-workers
prepared the cyclohexyl-fused tritosamide 3 in only 28% yield
using cyclohexyl ditosamide 4 with ditosyl ester 5 in DMF with
potassium carbonate.19b After completion of our synthetic studies,
Watkinson and co-workers also reported modest yields in the
macrocyclisation of cyclohexyl ditosamide 4 and tosyl ester 5.19d
This latter group attributed the moderate macrocyclisation yield
to geometric constraints as a result of ring strain. However, it
had been previously documented that macrocyclisations of 1,2-
ditosamides to provide tritosylamides of 1,4,7-triazacyclononanes
do so in only modest yield.18c,24 Searle and Geue concluded that
these low yields were a consequence of inhibition of the first substi-
tution step, that is the reaction of a bis-anion of a 1,2-ditosamide
with ditosyl ester 5. It was postulated that this inhibition may have
been due to steric and/or electronic effects in the 1,2-ditosamide
bis-anion.24 Searle and Geue were, however, able to carry out
successful macrocyclisations provided that 1,2-ditosamides were
not used as the source of the nucleophilic component. Instead,
an alternative disconnection involving classical Richman–Atkins
cyclisations with ethylene glycol ditosylate and the tritosamide
from diethylenetriamine provided good cyclisation yields.
Results and discussion
Our alternative approach to the synthesis of cyclohexyl-fused
tritosamide 3, via route B (Scheme 1), started from the racemic cy-
clohexyl diamine ( )-9 which was monotosylated using 0.31 equiv-
alents of tosyl chloride which gave the amino tosyl amide ( )-10
[83% based on limiting tosyl chloride, 27% based on ( )-9]
(Scheme 2).25 A two-step conversion of ethanolamine 11 into tosyl
aziridine 12 (70% over two steps) was carried out using a modifica-
tion of the method of Bulkowski and co-workers.26 Bulkowski and
co-workers had reported the effective ring opening of aziridine
12 with 1,2-amino tosamides.26 Analogous ring opening of the
aziridine 12 with amino tosyl amide ( )-10 in toluene at reflux
afforded the ditosamide amine ( )-13 (45%). This ring opening
was sluggish (60 h) and may reflect the hindered nature of the
amino functionality in amino tosyl amide ( )-10. N-Tosylation
of ditosamide amine ( )-13 with tosyl chloride in pyridine
smoothly afforded the tritosamide ( )-6 (72%). Ritchman-Atkins
Scheme 1
Scheme 2 Reagents and conditions: i, 0.31 equiv. TsCl, CH2Cl2, 3 N
NaOH, 0 ◦C, 83% [27% based on ( )-9]; ii, 2 equiv. TsCl, Py, 73%;
iii, NaH, THF, 96%; iv, toluene, D, 45%; v, TsCl, Py, 72%; vi, (a) NaH,
DMF, 25 ◦C, (b) (CH2OTs)2, 80 ◦C, 67%.
The focus for this study was to investigate alternative cyclisation
routes to the cyclohexyl-fused tritosamide 3 (Scheme 1). After
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macrocyclisation by treatment of tritosamide ( )-6 with two
equivalents of sodium hydride together with ethylene glycol dito-
sylate readily gave the target macrocycle tritosamide ( )-3 (67%).
The yield obtained in the macrocyclisation of tritosamide
( )-6 (67%) (Scheme 1, Route B) is very much in line with
the yields of other Richman–Atkins cyclisations (53–83%) us-
ing tritosamides and ethylene glycol ditosylate to give 1,4,7-
triazacyclonane derivatives.11,18e,21,22,24,27 This observation does not
appear to support the conclusions of Watkinson et al. that the
poor yields in the macrocyclisation of ditosamide 4 with ditosyl
ester 5 to give macrocycle 3 (Scheme 1, Route A) are a consequence
of geometric constraints from ring strain. Both Routes A and B
(Scheme 1) proced via the common intermediate 8, and our results,
therefore, indicate that cyclisation of anion 8 is not particularly
hindered. However, the sluggish reaction between aziridine 12 with
amino tosyl amide ( )-10 may suggest that the first substitution
step of the dianion of ditosamide 4 by ditosyl ester 5 is hindered.
Although Richman–Atkins macrocyclisation of cyclohexyl tri-
tosamide ( )-6 efficiently gave the cyclohexyl-fused macrocycle
tritosamide ( )-3, the overall yield was unacceptably low (5.86%)
over four steps. This is a consequence of the low yield in
two steps: firstly, in the monotosylation of diamine ( )-9 [83%
based on limiting tosyl chloride, 27% based on ( )-9]; and
secondly, in the ring opening of aziridine 12 with amino tosyl
amide ( )-10 (45%) (Scheme 2). Consequently, we decided to
re-investigate the reactions of 1,2-ditosamides with tosyl ester 5
(Scheme 1, Route A). Thus, the 1,2-diamines ( )-9 and 15a–c
were converted into the corresponding 1,2-ditosamides ( )-4 and
With access to the 1,2-ditosamides 4 and 16a–c in hand, we
investigated the macrocyclisation with tosyl ester 5 (Scheme 4,
Table 1). In the first instance, we repeated the macrocyclisation
of cyclohexyl ditosamide ( )-4 and tosyl ester 5 as previously
reported by Golding et al.19b In this case, a yield of 18% was
achieved for macrocycle ( )-3, in broad agreement with the yields
observed by Golding et al. (28%)19b and Watkinson and co-workers
(20%)19c (Table 1, entry 1, method A). In contrast, Beller et al. had
used the sodium salt of cyclohexyl (R,R)-4 with tosyl ester 5, which
cyclised to provide cyclohexyl-fused macrocycle (R,R)-3 in 68%.19a
In our hands, this cyclisation gave cyclohexyl-fused (R,R)-3 in a
disappointing 23%, identical to that observed by Watkinson and
co-workers19c (Table 1, entry 2, method B).
i
16a–c (68–79%) using tosyl chloride and base (Et3N or PrNEt2)
(Scheme 3). Additionally, the enantiopure (R,R)-4 was prepared
by resolution of 1,2-diamine ( )-9 via the tartrate salt 14 (85%).28
Subsequent ditosylation of the salt 14, using a modification of the
monotosylation conditions of Walsh and co-workers,29 afforded
the enantiopure cyclohexyl ditosamide (R,R)-4 (85%).19b,c
Scheme 4 Reagents and conditions: i, (method A) K2CO3, DMF, 50 ◦C,
7 d; ii, (method B) (a) NaOEt, EtOH (b) 5, DMF, 100 ◦C; iii, (method C)
(a) 2 equiv. NaH, DMF, (b) 5, DMF, 70 ◦C; iv (method D) disodium salt
of 16a, 5, DMSO, 100 ◦C; v, (method E) (a) 2 equiv. LiH, DMF, 70 ◦C,
(b) 5 or 18, DMF, 50 ◦C, 7 d.
The low yields observed in the macrocyclisation of 1,2-
ditosamide 4 and ditosyl ester 5 taken together with the inefficient
formation of cyclohexyl ditosamide amine ( )-13 from amino
tosyl amide ( )-10 and aziridine 12 (Scheme 2) initially suggested
that steric hindrance in both cyclohexyl 1,2-ditosamide 4 and
amino tosyl amide ( )-10 may have been a problem. In order to
understand these issues we chose to investigate the less sterically
demanding propane-1,2-ditosamide ( )-16a as the source of the
nucleophile in macrocyclisation. Given the previous success of
the macrocyclisation conditions using two equivalents of sodium
hydride in the formation of cyclohexyl-fused azamacrocycle ( )-3
from 1,4,7-tritotosamide ( )-13 (Scheme 1, Route B), we decided
to use sodium hydride in DMF with propane-1,2-ditosamide
( )-16a.24 Thus, cyclisation of propane-1,2-ditosamide ( )-16a
under these conditions (conditions C, Table 1) with ditosyl ester
5 gave the mono-substituted macrocycle ( )-17a in a meagre 10%
(entry 3, Table 1). This observation was in line with the results
i
Scheme 3 Reagents and conditions: i, TsCl, Et3N or PrNEt2, CH2Cl2,
68–79%; ii, (a) L-(+)-(2R,3R) tartaric acid, 70 ◦C, (b) AcOH, 90 ◦C, 85%;
iii, TsCl, 1.2 N NaOH, CH2Cl2, 85%.
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Table 1 Investigation of macrocyclisation methods using 1,2-ditosamides 4 and 16a–c with sulfonates 5 and 18 (Scheme 4)
Entry Ditosamide (R1, R2)
Electrophile (P)
Methoda
Macrocyclic product (R1, R2)
Yield (%) (Lit. Yield (%))
1
2
3
4
5
6
7
8
9
(
(
(
(
(
)-4 (R1 = R2 = (CH2)4)
5 (R = SO2C6H4CH3)
A
B
C
D
B
Cb
E
E
E
E
E
(
(
(
(
(
)-3 (R1 = R2 = (CH2)4)
18 (28,19b 2019c
)
)
)- or (R,R)-4 (R1 = R2 = (CH2)4) 5 (R = SO2C6H4CH3)
)- or (R,R)-3 (R1 = R2 = (CH2)4) 23 (68,19a 2319c
)-16a (R1 = CH3, R2 = H)
)-16a (R1 = CH3, R2 = H)
)-16a (R1 = CH3, R2 = H)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
5 (R = SO2C6H4CH3)
18 (R = SO2C6H4NO2)
)-17a (R1 = CH3, R2 = H)
)-17a (R1 = CH3, R2 = H)
)-17a (R1 = CH3, R2 = H)
10
(2018d
)
)
(6018a
16b (R1 = R2 = H)
17b (R1 = R2 = H)
(2524)
91
16b (R1 = R2 = H)
17b (R1 = R2 = H)
(
)-16a (R1 = CH3, R2 = H)
(
)-17a (R1 = CH3, R2 = H)
60
0
65–70
57
(R,R)-16c (R1 = R2 = Ph)
(R,R)-4 (R1 = R2 = (CH2)4)
(R,R)-4 (R1 = R2 = (CH2)4)
(R,R)-17c (R1 = R2 = Ph)
(R,R)-3 (R1 = R2 = (CH2)4)
10
11
(
)-19 (R1 = R2 = (CH2)4)
a Method A: K2CO3, DMF, 50 ◦C; method B: (a) NaOEt, EtOH, (b) 5, DMF, 100 ◦C; method C: (a) 2 equiv. NaH, DMF, (b) 5, DMF, 70 ◦C; method
D: disodium salt of 16a, 5, DMSO, 100 ◦C; method E: (a) 2 equiv. LiH, DMF, 70 ◦C (b) 5 or 18, DMF, 50 ◦C. b Cyclisation step carried out at 105 ◦C.
of Graham and Weatherburn18d who cyclised the disodium salt
of propane ditosamide( )-16a with ditosyl ester 5 in DMSO at
100 ◦C which gave the macrocycle ( )-17a in 20% yield (entry 4,
Table 1, method D). This is in contrast to the findings of Mason
and Peacock who claimed a 60% yield of macrocycle (R)-17a by
reaction of the disodium salt of (R)-16a and ditosyl ester 16a using
DMF at 100 ◦C (entry 5, Table 1).18a However, even with the less
sterically demanding ethane-1,2-ditosamide 16b Searle and Geue
formed the parent 1,4,7-tritosyl-1,4,7-triazacyclononane 17b in
only 25% using two equivalents of sodium hydride in DMF at
105 ◦C (entry 6, Table 1).24 Indeed, it was Searle and Geue who first
delineated the problems in the formation of 1,4,7-tritosyl-1,4,7-
triazacycloalkanes using dianions of 1,2-ditosamides. These work-
ers postulated that steric and/or electronic effects inhibit the first
nucleophilic substitution step in the reaction of 1,2-ditosamide
dianions with bis-electrophiles (cf. Route A, Scheme 1). The lack of
a clear correlation of yield of macrocycle with the anticipated steric
encumbranceof 1,2-ditosamides 4 and 16a in our results (entries 1–
3, Table 1) argues against just steric effects. However, electronic
effects, solubility and nucleophilicity of 1,2-ditosamide dianions
remained as possible causes for low yields in macrocyclisations.
In the context of the above issues of cyclisation of dianions of
1,2-ditosamides we wondered if alternatives to the sodium counte-
rion might be helpful in developing efficient routes to cyclohexyl-
fused macrocycle 3 via 1,2-ditosamides (Route A, Scheme 1). In
this context, caesium carbonate has been found to be beneficial
in Richman–Atkins cyclisations30 and in macrolactonisations.31
These observations were rationalised in terms of the basicity of
caesium bicarbonate30 and in terms of ion-paring properties of
caesium salts31 rather than a templating effect of the caesium
cation. However, in related macrocyclisations of cyclohexyl di-
tosamide 4 using caesium carbonate we had observed poor yields
of macrocycles.32 This suggested that ion-pairing properties of
salts of cyclohexyl ditosamide 4 may not be the source of low
macrocyclisation yields. We wondered, from our experimental
observations, if solubility of dianions of 1,2-ditosamides might
be an issue with low macrocyclisation yields.
molecules around the small lithium cation that has a large surface
+
−3 33
˚
to charge density (Li 0.13 Z A ). Therefore, we hoped that the
use of lithium counterions in dianions of 1,2-ditosamides would
provide for a more effective macrocyclisation. Unfortunately,
lithium carbonate is not basic enough to deprotonate secondary
tosamides30 but we anticipated that lithium hydride might result
in effective macrocyclisations of 1,2-ditosamides. Accordingly,
treatment of ethylene 1,2-ditosamide 16b with two equivalents
of lithium hydride in DMF at 70 ◦C followed by addition of
ditosyl ester 5 at 50 ◦C gave the parent 1,4,7-tritosyl-1,4,7-
triazacyclononane 17b in an unprecedented 91% yield (entry 7,
Table 1). To explore the scope of this process we investigated the
use of propyl 1,2-ditosamide ( )-16a and diphenyl 1,2-ditosamide
(R,R)-16c (entries 8 and 9, Table 1). The former provided the
methyl-substituted macrocycle 17a in 60% yield while the latter
failed to afford the diphenyl macrocycle 17c. Clearly, there is a
complex interplay of steric and counterion effects at work in these
macrocyclisations. The use of lithium as the cation enables some of
these cyclisations to proceed efficiently. However, the decrease in
yield on increasing the steric requirements of the 1,2-ditosamide
(entries 7 and 8, Table 1) indicates that the macrocyclisation is
subject to some steric hindrance factors. With these observations in
mind we then investigated the key macrocyclisation of cyclohexyl
ditosamide (R,R)-4 with ditosyl ester 5. Satisfyingly, the cyclohexyl
macrocycle (R,R)-3 was obtained in consistently good yields
(65–70%) (entry 10, Table 1).§ Since 4-nitrosulfonamides (nosyl;
Nos) have been used in heterocyclic cyclisations34 and the nosyl
group can be removed under mild conditions we investigated our
cyclisation protocol with cyclohexyl ditosamide ( )-4 and bisnosyl
ester 18. This macrocyclisation gave the ditosamide nosyl amide
19 in 57% yield (entry 11, Table 1).
The efficient macrocyclisation of 4 with 5 (Scheme 4) suggests, in
contrast to the observations of Watkinson and co-workers,19c,d that
the cyclohexyl macrocycle 3 is not subject to undue ring strain to
prevent macrocyclisation. Indeed, this approach presents a much
more effective synthesis of 3 (two steps from salt 14, 55% overall)
in contrast to Route A (Scheme 1) (four steps, 5.86% overall)
Having established an effective route to the chiral macrocycle
(R,R)-3 (Schemes 3 and 4) we wished to prepare metal complexes
Lithium salts are markedly different from the other alkali
metal salts.33 Unlike the latter, the salts lithium chloride and
lithium bromide are somewhat soluble in polar organic solvents
such as alcohols and ethers. The solubility of these salts can
be attributed to the relatively strong coordination of solvent
§ Three separate workers in these laboratories have achieved consistent
yields in the synthesis of (R,R)-3.
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of the corresponding N-alkyl derivatives. Thus, deprotection of
the chiral macrocyclic tritosylamide (R,R)-3 was accomplished via
using lithium in ammonia,18e which afforded the hydrochloride salt
(R,R)-20 (73%) (Scheme 5). The macrocyclic amine hydrochloride
(R,R)-20 was converted into its free base (R,R)-2 with aqueous
NaOH. Methylation of the free base (R,R)-2 was conveniently
achieved using the Eschweiler–Clarke N-methylation procedure
which afforded the N-methyl macrocycle (R,R)-1 (79%).35
preparing complex 21 is perhaps reflected in the meagre yield
(18%) reported for the preparation of the hexafluorophosphate
salt of 21.19a
Undeterred by our experiences in preparing (l-oxo)-bis(l-
acetoxy)-dimanganese complexes we then explored the prepara-
tion of copper(II) complexes of (R,R)-1. Thus, treatment of (R,R)-
1 with copper(II) chloride in acetonitrile followed by addition
of silver trifluoroacetate afforded blue crystals of 22 (53%)
(Scheme 5).17 The crystalline nature of copper(II) complex 22
allowed an X-ray analysis to be carried out: this enabled both
the stereochemistry and the absolute structure to be confirmed
unequivocally by single crystal diffraction (Fig. 1).ꢀ
Fig. 1 ORTEP representation of complex 22. Hydrogen atoms are
omitted for clarity.
The closest known structure to complex 22 is that of a copper
complex of an analogous 4-oxa-1,7-diazonane (N,N,O) ligand,
[CuCl2(C10H18N2O)] 23.19c
Scheme 5 Reagents and conditions: i, (a) Li, NH3, EtOH, (b) aq. HCl
(73%); ii, (a) aq. NaOH, (b) HCO2H, HCHO, D, 24 h (79%); iii, Mn(OAc)3,
MeOH–H2O (9 : 1), NaClO4; iv, (a) CuCl2, CH3CN (b) AgO2CCF3.
The complex 23 adopts a square planar structure (all angles about
Cu are within 10◦ of ideal 90 and 180◦ values) with a longer
˚
contact to O (average Cu · · · O distance 2.335 A) giving a pseudo
square pyramidal geometry. In 22, although one Cu–N distance
With adequate quantities of chiral macrocycle (R,R)-1 in hand,
we wished to prepare the (l-oxo)-bis(l-acetoxy) perchlorate salt
21 and derivatives. The corresponding hexafluorophosphate salt
of 21 had been prepared by Beller et al.,19a albeit in 18%
yield. Beller et al. used the hexafluorophosphate salt of 21 as
well as the corresponding tris(l-oxo) complex in the impressive
enantioselective epoxidation of alkenes (8–92% ee).8
Wieghardt et al. had originally developed the synthesis of (l-
oxo)-bis(l-acetoxy)-dimanganese complexes of the parent macro-
cycle 1,4,7-trimethyl-1,4,7-triazacyclononane.36 However, using
the modified method of Wieghardt and Weyhermu¨ller37 with
(R,R)-1 failed to give any of complex 21.¶ The difficulty in
is longer than the others [compare 2.195(2) with 2.033(3) and
˚
2.094(2) A] the difference is not so marked as in 23. In 22 there
is also some distortion away from square pyramidal and towards
trigonal bipyramidal geometry, with O1 and N1 axial. Complete
well for (l-oxo)-bis(l-acetoxy)-dimanganese complexes of 1,4,7-trimethyl-
1,4,7-triazacyclononane (58%). However, using (R,R)-1, material with a
low carbon, hydrogen and nitrogen content was isolated.
ꢀ Crystal data for 22: C17H27CuF6N3O4, Mr = 514.96, orthorhombic, space
˚
group P212121, a = 8.3666(2), b = 15.4945(3), c = 16.3029(4) A, V =
2133.45(8) A , Z = 4, qcalc = 1.618 g cm−3, Mo-Karadiation, k = 0.71073 A,
l = 1.115 mm−1, T = 173 K; 30 600 reflections were collected, 4836 were
unique, Rint 0.077; final refinement to convergence on F2 with all non-H
atoms anisotropic gave R = 0.0405 (F, 3771 obs. data only) andRw = 0.0719
(F2, all data), GOF = 1.033, for 283 refined parameters. Residual electron
3
˚
˚
¶ We are indebtited to Dr Thomas Weyhermu¨ller (Max Planck Institute
for Bioorganic chemistry, Mulheim, Germany) for providing the details of
these modified conditions.37 In our hands, this process worked extremely
density max. and min. 0.331 and −0.301 e A−3. Flack parameter refined
˚
to −0.001(1) indicating the correct assignment of absolute configuration.
378 | Org. Biomol. Chem., 2008, 6, 374–384
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adoption of trigonal bipyramidal geometry is hindered by the
polydentate ligand imposing small (< 90◦) NCuN angles. The
N3CuO3, N2CuO3 and N2CuN3 angles, 152.36(9), 124.75(9)
and 82.87(9)◦ respectively, emphasise the distorted nature of the
resulting structure.
Experimental
Synthetic studies via Route A
(
)-4-Methyl-N -(2-{[(4-methylphenyl)sulfonyl]amino}cyclo-
hexyl) benzenesulfonamide 4. To a solution of ( )-1,2-diamino-
cyclohexane 9 (1.20 g, 10.5 mmol), diisopropylethylamine (7.3 cm3,
67 mmol, 6.4 equiv.) in DCM (10 cm3) was added p-toluenesulfonyl
chloride (4.0 g, 21 mmol, 2 equiv.) in batches over 30 min at
0 ◦C. The reaction was continued for an additional 12 h at room
temperature. On completion, the reaction was quenched with
2 M HCl (20 cm3). The aqueous mixture was extracted with
diethyl ether (×3, 20 cm3) and the combined organic extracts
were dried (Na2SO4), filtered and evaporated to form the crude
dark brown oil. Purification by column chromatography on silica
(hexane–EtOAc–CH2Cl2 4 : 1 : 5) afforded a white solid (3.0 g,
7.1 mmol, 68%); mp 180–181 ◦C. Found: C, 56.7; H, 6.1; N, 6.6;
S, 15.2%; MH+ 423.1427. Calculated for C20H26O4S2N2: C, 56.9;
H, 6.2; N, 6.6; S, 15.2%; MH+ 423.1412. mmax (KBr, cm−1) 3256
(s, NHTs), 3055 (w, C6H4), 2925 (m, CH), 2856 (m, CH), 1333 (s,
SO2NH), 1161 (s, SO2NH); dH (400 MHz, CDCl3), 1.09 (m, 4H,
2 × CH2), 1.53 (m, 2H, CH2), 1.81 (m, 2H, CH2), 2.75 (m, 2H,
2 × CHNHTs), 4.98 (m, 2H, 2 × NHTs), 7.31 (d, J 8.3 Hz, 4H,
C6H4CH3), 7.76 (d, J 8.3, 4H, C6H4CH3); dC (100 MHz, CDCl3)
21.7 (C6H4CH3), 21.9 (C6H4CH3), 24.0 (CH2), 26.5 (CH2), 31.0
(CH2), 35.3 (CH2), 54.9 (CH), 66.3 (CH), 127.3 (4 × ArCH), 129.7
(4 × ArCH), 139.6 (2 × ArC), 143.3 (2 × ArC).
With an efficient synthesis of (R,R)-cyclohexyl macrocycle 1
developed and the preparation of the corresponding copper(II)
complex 22 in hand we turned our attention to the use of the
latter in the aziridination of styrene. Thus, catalyst 22 (5 mol%)
and PhNITs (1 equivalent) sluggishly catalysed the aziridination of
styrene 24 (10 equiv.) to afford the aziridine 25 (49%) (Scheme 6).
Disappointingly, analysis of the aziridine 25 by chiral HPLC
indicated that racemic material had been obtained. The sluggish
catalysis by 22 together with the production of racemic aziridine
25 suggests that C-substitution of the azamacrocycle ring inhibits
the catalysis without establishing an effective chiral pocket. This
observation is supported by our experiences in the use of chiral
azamacrocycles in epoxidation processes.11,32
Scheme 6 Reagents and conditions: i, 5 mol% 22, CH3CN, RT.
Conclusions
Classical Richman–Atkins macrocyclisation of tritosamide 6 with
ethylene glycol ditosylate 7, efficiently gave the cyclohexyl-fused
macrocycle 3. In contrast to published views, this indicated
that macrocycle 3 was not unduly strained. Inefficiencies in the
preparation of tritosamide 6 led to a re-investigation of a more
direct macrocyclisation using 1,2-ditosamides. In agreement with
long-standing literature precedence, initially, these cyclisations
were inefficient. However, a new protocol was developed that used
lithium salts of 1,2-ditosamides, generated in situ, to improve the
solubility of these nucleophilic components. The improved solu-
bility of these lithium salts of 1,2-ditosamides over their sodium
salt counterparts led to dramatic improvements in the macrocycli-
sation yields. These improved yields were still subject to a degree
of steric effects depending on the nature of the a-substituents in
the 1,2-ditosamides 4 and 16a–c. The 1,2-ditosamide 16b, lacking
an a-substituent, gave the unsubstituted 1,4,7-triazacyclononane
17b in exceptional 91% yield using our modified macrocyclisation
procedure. A single methyl a-substituent in 1,2-ditosamide 16a
led to a drop in the macrocyclisation efficiency, with methyl
1,4,7-triazacyclononane 17a being produced in 60% yield. How-
4-Methyl-N -(1-methyl-2-{[(4-methylphenyl)sulfonyl]amino}-
ethyl)benzenesulfonamide 16a. The title compound 16a was
prepared in a similar manner to 4 using ( )-1,2-propanediamine
15a (2 cm3, 1.74 g, 23.5 mmol), triethylamine (17 cm3, 12.34 g,
122 mmol, 5.2 equiv.) and p-toluenesulfonyl chloride (10.00 g,
52.6 mmol mmol). The crude product was filtered through silica
(6 × 5 cm3) which gave a gum that was precipitated from ethanol
using diethyl ether. Recrystallisation from ethanol gave the title
compound 1◦6a as large long needles (7.73 g, 20.2 mmol, 86%);
mp 106–108 C (lit.38 103–104 ◦C). Found: C, 53.4; H, 5.8; N, 7.2;
S, 16.7%; MH+ 383.1099. Calculated for C17H22N2O4S2: C, 53.4;
H, 5.8; N, 7.3; S, 16.8%; MH+ 383.1099. mmax (KBr, cm−1) 3303
(s, NHTs), 2925 (m, CH), 2978 (w, CH), 1598 (w, C6H4), 1322 (s,
SO2NH), 1159 (s, SO2NH), 814 (s, C6H4); dH (400 MHz, CDCl3)
0.97 (d, J 6.4 Hz, 3H, CH3), 2.40 (s, 6H, 2 × H CH3), 2.82–2.88
(m, 1H, CHH), 2.91–2.98 (m, 1H, CHH), 3.27–3.36 (m, 1H, CH),
5.23 (d, J 7.6, 1H, NH), 5.36 (d, J 6.4, 1H, NH), 7.25–7.28 (m, 4H,
C6H4CH3), 7.65–7.74 (m, 4H, C6H4CH3); dC (100 MHz, CDCl3)
18.8 (CH3), 21.6 (CH3), 21.7 (CH3), 48.5 (CH2N), 49.7 (CHN),
127.2, 127.3, 129.9, 130.0 (all 2 × C6H4CH3), 136.9 and 137.4
(both ArC), 143.6 and 143.8 (both ArC).
ꢁ
ever, an a,a -disubstitution pattern in the 1,2-ditosamide was
ꢁ
as efficient provided that the a,a -substituents were not too
sterically demanding. So, trans-cyclohexyl-1,2-ditosamide (R,R)-
4 gave the cyclohexyl-fused 1,4,7-triazacyclonanone (R,R)-3 in
4-Methyl-N-(2-{[(4-methylphenyl)sulfonyl]amino}ethyl)benzene-
sulfonamide 16b. The title compound 16b was prepared in a
similar manner to 4 using ethylenediamine 15b (3 cm3, 44 mmol),
triethylamine (32 cm3, 0.224 mol) and p-toluenesulfonyl chloride
(18.8 g, 98 mmol). Addition of diethyl ether gave a precipitate
that was collected by filtration and washed with hexane. The
crude product 16b (12.60 g, 0.034 mol, 76%) was pure enough for
the next step; mp 163–164 ◦C (lit.24 162–164 ◦C). Found: C, 52.1;
H, 5.5; N, 7.8; S, 17.4%. Calculated for C16H20N2O4S2: C, 52.2;
H, 5.5; N, 7.6; S, 17.4%. mmax (KBr, cm−1) 3289 (s, TsNH), 3076
ꢁ
65–70% yield. In contrast, the sterically demanding a,a -diphenyl
1,2-ditosamide 16 failed to give any macrocycle. The efficiency
of this macrocyclisation protocol allowed the synthesis of useful
quantities of chiral cyclohexyl-fused azamacrocycle 3. Subsequent
deprotection, N-methylation of the chiral cyclohexyl-fused aza-
macrocycle 3 followed by copper(II) complex formation led to the
preparation of the new chiral copper(II) complex 22. Although
complex 22 sluggishly catalysed the aziridination of stryrene, it
did so in a racemic fashion.
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(w, C6H4), 2928, (m, CH), 2884 (m, CH), 1333, (s, SO2NH), 1156
(s, SO2NH); dH (400 MHz, CDCl3) 2.37 (s, 6H, C6H4CH3), 2.70
(s, 4H, CH2), 7.37 (d, J 8.0 Hz, 4H, C6H4), 7.60 (d, J 8.0, 4H,
C6H4); 13C NMR (CD3SOCD3) dC 21.4 (C6H4CH3), 42.6 (CH2N),
126.8, 130.1 (all C6H4CH3), 137.7, 143.2 (both ArC).
CH2), 1.53–1.55 (m, 2H, CH2), 1.81–1.84 (m, 2H, CH2), 2.42
(s, 6H, 2 × C6H4CH3), 2.75–2.77 (m, 2H, 2 × ArSO2NHCH),
4.95–5.00 (m, 2H, 2 × ArSO2NHCH), 7.30 (d, J 8.3 Hz, 4H,
2 × C6H4CH3), 7.75 (d, J 8.3, 4H, 2 × C6H4CH3); dC (400 MHz,
CDCl3) 21.7 (2 × C6H4CH3), 24.3 (2 × CCH2C), 33.3 (2 ×
CCH2C), 56.7 (2 × NHCH), 127.4 (4 × C6H4CH3), 129.9 (4 ×
C6H4CH3), 137.2 (2 × ArC), 143.7 (2 × ArC).
4-Methyl-N-((1R,2R)-2-{[(4-methylphenyl)sulfonyl]amino}-1,2-
diphenylethyl)benzenesulfonamide 16c. The title compound 16c
was prepared according to the method of Corey et al.39 using
(1R,2R)-1,2-diphenyl-1,2-ethanediamine 15c (1.08 g, 5.07 mmol),
triethylamine (3.5 cm3, 25.1 mmol), N,N-dimethylaminopyridine
(25 mg, 0.2 mmol) and p-toluenesulfonyl chloride (2.18 g,
11.4 mmol). Recrystallisation from ethanol gave the title
compound 16c as fine white needles (2.35 g, 4.5 mmol, 89%); mp
2-[[(4-Methylphenyl)sulfonyl](3-{[(4-methylphenyl)sulfonyl]-
oxy}propyl)amino]ethyl-4-methylbenzenesulfonate 5. The title
compound was prepared according to the method of Searle
and Geue24 using diethanolamine (1.00 g, 9.5 mmol) and p-
toluenesulfonyl chloride (4.00 g, 21 mmol) which gave a crude
dark brown oil. Purification by column chromatography on silica
(hexane–EtOAc–CH2Cl2 4 : 1 : 5) afforded a white solid (3.20 g,
5.7 mmol, 60%); mp 94–96 ◦C (lit.24 96–98 ◦C). Found: C, 53.1; H,
5.2; N, 2.5; S, 16.7%; MH+ 568.1144. Calculated for C25H30O8S3N:
C, 52.9; H, 5.2; N, 2.5; S, 16.9%; MH+ 568.1134. mmax (KBr, cm−1)
3062 (w, C6H4), 2952 (m, CH), 1357 (s, SO2NH), 1174 (s, SO2OR),
1158 (s, SO2NH); dH (400 MHz, CDCl3) 2.42 (s, 3H, C6H4CH3),
2.47 (s, 6H, C6H4CH3), 3.38 (t, J 5.9 Hz, 4H, CH2NTs), 4.12 (t,
J 5.9, 4H, CH2OTs), 7.29 (d, J 8.0, 2H, C6H4CH3); 7.35 (d, J
8.0, 4H, C6H4CH3); 7.63 (d, J 8.0, 2H, C6H4CH3); 7.78 (d, J 8.0,
4H, C6H4CH3); dC (100 MHz, CDCl3) 21.7 (C6H4CH3), 21.8 (2 ×
C6H4CH3), 48.7 (2 × CH2NTs), 68.5 (2 × CH2OTs), 127.5 (2 ×
ArCH), 128.2 (4 × ArCH), 130.1 (4 × ArCH), 130.2 (2 × ArCH),
132.7 (2 × ArC), 135.5 (ArC), 144.4 (ArC), 145.4 (2 × ArC).
◦
209–210 C (lit.40 202 ◦C); [a]D = 40.5 (c = 1.76, CHCl3) (lit.39
[a]D = 43.9 (c = 1.74, CHCl3). Found: C, 64.8; H, 5.3; N, 5.6;
S, 13.4%. Calculated for C28H28N2O4S2: C, 64.6; H, 5.4; N, 5.4;
S, 12.3%. dH (400 MHz, CDCl3) 2.31 (s, 6H, 2 × C6H4CH3),
4.51–4.56 (ABX m, 2H, 2 × CHNH), 5.89–5.95 (ABX m 2H,
2 × NH), 6.71 (d, J 8.0 Hz, 4H, C6H4CH3), 6.99–7.05 (m, 10H,
C6H5), 7.47 (d, J 8.0, 4H, C6H4CH3); dC (100 MHz, CDCl3) 21.6
(2 × C6H4CH3), 62.5 (2 × CHNH), 127.3 (4 × ArCH), 127.7
(2 × ArCH), 127.8 (4 × ArCH), 128.2 (4 × ArCH), 129.0 (4 ×
ArCH), 136.5 (2 × ArC), 137.2 (2 × ArC), 143.3 (2 × ArC).
Using the chiral shift reagent Eu(hfc)2 indicated an ee ꢀ 99%.
(1R,2R)-1,2-Cyclohexanediaminium (2R,3R)-2,3-dihydroxy-
butanedioate 14. The title compound 14 was prepared according
to the method of Jacobsen and co-workers.28 Thus, using ( )-1,2-
cyclohexanediamine 9 (24 cm3, 0.2 mol), L-tartaric acid (15.00 g,
0.1 mol) and glacial acetic acid (10 cm3, 0.175 mol) gave the
title compound 14 as a white solid (21.73 g, 82 mmol, 85%). An
analytical sample was obtained by recrystallisation from water,
2-[[(4-Nitrophenyl)sulfonyl](2-{[(4-nitrophenyl)sulfonyl]oxy}-
ethyl)amino]ethyl 3-nitrobenzenesulfonate 18. To a stirred solu-
tion of diethanolamine (587 mg, 5.69 mmol) and◦triethylamine
(2.8 cm3, 20 mmol) in anhydrous THF (14 cm3) at 0 C under a ni-
trogen atmosphere was added portionwise, 4-nitrobenzenesulfonyl
chloride (4.10 g, 18.7 mmol). This mixture was stirred at 0 ◦C for
1 h then at room temperature for 18 h. At the conclusion of this
period the reaction mixture was concentrated at reduced pressure
(20 mm Hg). The residue was dissolved in dichloromethane
(20 cm3), washed with water (25 cm3), dried (Na2SO4), filtered
and evaporated to afford an orange solid. Recrystallisation from
methanol–THF gave the title compound 18 (2.42 g, 3.66 mmol,
65%) as colourless needles; mp 131–134 ◦C. Found: C, 40.1;
◦
which afforded colourless plates; mp 252.5–256 C (lit.40 252–
255 ◦C); [a]D = +12.2 (c = 1, H2O) [lit.23 [a]D = +12.4 (c = 2, H2O)].
Found: C, 45.5; H, 7.6; N, 10.4%. Calculated for C10H20N2O6: C,
45.5; H, 7.6; N, 10.6%.
4-Methyl-N-((1R,2R)-2-{[(4-methylphenyl)sulfonyl]amino}cyclo-
hexyl)benzenesulfonamide (R,R)-4. To a stirred solution of
+
(1R,2R)-1,2-cyclohexanediaminium
(2R,3R)-2,3-dihydroxy-
H, 2.9; N, 8.3%; MNH4 678.0482. C22H20N4O14S3 requires: C,
butanedioate 14 (11.20 g, 42.4 mmol) in distilled water (150 cm3)
and sodium hydroxide (7.10 g, 177.7 mmol) at 0 ◦C under
a nitrogen atmosphere was added dropwise a solution of p-
toluenesulfonyl chloride (16.99 g, 89.1 mmol) in dichloromethane
(100 cm3) over a 1 h period. The reaction mixture was allowed
to warm to room temperature and then stirred for 18 h. At
the completion of this period the phases were separated and
the aqueous phase was extracted with dichloromethane (2 ×
100 cm3). The combined organic extracts were washed with
brine (5 cm3), dried (Na2SO4), filtered and evaporated to afford
a white foam (20.54 g). Recrystallisation from methanol gave
the title compound (15.30 g, 36.14◦mmol, 85%) as a colourless
40.0; H, 3.0; N, 8.5%; MNH4 678.0476. mmax (KBr, cm−1) 3108
+
and 3041 (w, C6H4), 2936 (w, CH), 1530 (s, C6H4NO2), 1366 (s,
SO2N), 1352 (s, OSO2), 1312 (s), 1184 (s, SO2); dH (400 MHz,
CD3NO2) 3.54–3.62 (m, 4H, 2 × CH2OSO2), 4.23–4.31 (m, 4H,
2 × CH2NSO2), 8.01 (d, J 8.0 Hz, 2H, C6H4SO2N), 8.13 (d, J 8.0,
4H, NO2C6H4SO2O), 8.34 (d, J 8.0, 2H, NO2C6H4SO2N), 8.44
(d, J 8.0, 4H, NO2C6H4SO2O); dC (100 MHz, CD3NO2) 49.1 (2 ×
CH2NSO2), 70.5 (4 × CH2OSO2), 125.9 (2 × C6H4), 126.0 (4 ×
C6H4), 130 (2 × C6H4), 130.8 (2 × C6H4), 142.1 (2 × ArC), 145.5,
152 and 152.7 (all ArC).
( )-1,4,7-Tris[(4-methylphenyl)sulfonyl]dodecahydro-1H-1,4,7-
benzotriazonine 3.
microcrystalline solid; mp 172–184 C (lit.41 167–168 ◦C); [a]D
=
12.2 (c = 2.04, CHCl3) [lit.40 [a]D = 9.76 (c = 2.06, CHCl3)]. Found:
C, 57.0; H, 6.1; N, 6.8; S, 15.1%. Calculated for C20H26N2O4S2: C,
56.9; H, 6.2; N, 6.6; S, 15.2%. mmax (KBr, cm−1) 3286 (s, TsNH),
3065 (w, C6H4), 2928 (m, CH), 2870 (m, CH), 1326 (s, SO2NH),
1162 (s, SO2NH); dH (400 MHz, CDCl3) 1.05–1.14 (m, 4H, 2 ×
(a) Method A (potassium carbonate in DMF) (Table 1, entry 1).
To ( )-4-methyl-N-(2-{[(4-methylphenyl)sulfonyl]amino}cyclo-
hexyl) benzenesulfonamide 4 (600 mg, 1.4 mmol) in DMF
(19 cm3) was added potassium carbonate (461 mg, 3.3 mmol). The
resulting suspension was heated to 50 ◦C for 1 h. On completion
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of this period
a
solution of 2-[[(4-methylphenyl)sulfonyl]-
( )-2-Methyl-1,4,7-tris[(4-methylphenyl)sulfonyl]-1,4,7-
(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)amino]ethyl-4-methyl-
benzenesulfonate 5 (990 mg, 1.7 mmol) in DMF (10 cm3) was
added dropwise over 24 h. The DMF was removed under
reduced pressure (12 mm Hg) and the residue was dissolved in
dichloromethane (15 cm3). The organic layer was washed with
water (×2, 20 cm3), dried (Na2SO4), filtered and evaporated to
give a off-white solid (520 mg). The off-white solid was dissolved in
ethanol (10 cm3) and heated to reflux for 2 h. The white precipitate
that formed was removed by filtration, washed with ethanol
(10 cm3) and dried under reduced pressure (0.1 mm Hg) to give the
title macrocycle ( )-3 as a white solid (162 mg, 0.25 mmol, 18%);
triazacyclononane 17a.
(a) Method C (sodium hydride in DMF) (Table 1, entry 3).
To a stirred solution of the 4-methyl-N-(1-methyl-2-{[(4-methyl-
phenyl)sulfonyl]amino}ethyl)benzenesulfonamide 16a (300 mg,
0.79 mmol) and 2-[[(4-methylphenyl)sulfonyl](3-{[(4-methyl-
phenyl)sulfonyl]oxy}propyl)amino]ethyl-4-methylbenzenesulfo-
nate 5 (443 mg, 0.78 mmol) in DMF (7 cm3) at 60 ◦C was added a
suspension of hexane washed sodium hydride (60% in oil, 65 mg,
1.63 mmol) in DMF (2 cm3) over a 3 h period. The reaction mixture
was then brought to 80 ◦C and maintained at that temperature for
a further 2 days. At the completion of this period the volatiles were
removed (12 mm Hg) and the residue was dissolved in ethyl acetate
(15 cm3). This solution was washed with water (2 × 15 cm3), dried
(Na2SO4), filtered and evaporated to afford an oil. Purification by
column chromatography using ethyl aceate–hexane (2 : 3) as the
eluant afforded an oil that precipated the title macrocycle from hot
ethanol as a white solid (47 mg, 0.08 mmol, 10%). The physical
and spectroscopic data were identical to those reported below
using method E.
◦
mp 260–262 C. Found: C, 57.7; H, 5.9; N, 6.2; S, 14.9%; MH+
646.2093. C31H39O6S3N3 requires: C, 57.7; H, 6.1; N, 6.5; S, 14.9%;
MH+ 646.2079. mmax (KBr, cm−1) 3065 (w, C6H4), 2928 (m, CH),
2865 (m, CH), 1326 (s, SO2NH), 1153 (s, SO2NH); dH (400 MHz,
CDCl3) 1.14 (m, 2H, CH2), 1.27 (m, 2H, CH2), 1.58 (m, 2H, CH2),
1.79 (m, 1H, CH2), 2.17 (m, 1H, CH2), 2.35 (s, 3H, C6H4CH3),
2.42 (s, 6H, C6H4CH3), 2.62 (m, 1H, CH2NTs), 3.07 (m, 1H,
CH2NTs), 3.28 (m, 3H, CH2NTs), 3.48 (m, 3H, CH2NTs), 3.75
(m, 1H, CHNTs), 4.89 (m, 1H, CHNTs), 7.29 (m, 6H, C6H4CH3),
7.61 (d, J 8.3 Hz, 2H, C6H4CH3), 7.76 (m, 2H, C6H4CH3), 8.00
(m, 2H, C6H4CH3); dC (100 MHz, CDCl3) 21.7 (3 × C6H4CH3),
24.7 (CH2), 26.1 (CH2), 29.0 (CH2), 30.3 (CH2), 47.1 (CH2NTs),
52.4 (CH2NTs), 55.0 (CH2NTs), 55.8 (CH2NTs), 60.2 (CHNTs),
68.2 (CHNTs), 127.3 (2 × ArCH), 127.9 (2 × ArCH), 128.7 (2 ×
ArCH), 129.7 (2 × ArCH), 129.9 (4 × ArCH), 130.1 (2 × ArC),
135.1 (ArC), 137.5 (ArC), 143.6 (ArC), 144.2 (ArC).
(b) Method E (lithium hydride in DMF) (Table 1, entry 8).
To a stirred suspension of lithium hydride (17 mg, 2.2 mmol) in
anhydrous DMF (10 cm3) at 0 ◦C was added a solution of 4-
methyl-N-(1-methyl-2-{[(4-methylphenyl)sulfonyl]amino}ethyl)-
benzenesulfonamide 16a (820 mg, 2.15 mmol) in DMF (2 cm3)
over a 20 min period. The resulting mixture was warmed to
room temperature, whereupon, a solution of 2-[[(4-methylphenyl)-
sulfonyl](3-{[(4-methylphenyl)sulfonyl]oxy}propyl)amino]ethyl-
4-methylbenzenesulfonate 5 (1.217 g, 2.1 mmol) in DMF (2 cm3)
was added dropwise over 1 h. The cloudy suspension was then
(b) Method B (sodium ethoxide in ethanol then DMF) (Table 1,
entry 2)19a. To a stirred suspension of ( )-4-methyl-N-(2-{[(4-
◦
methylphenyl)sulfonyl]amino}cyclohexyl)benzenesulfonamide
4
heated to 80 C and the final aliquot of lithium hydride (17 mg,
(500 mg, 1.2 mmol) in anhydrous ethanol (2 cm3) at reflux under
nitrogen was added a solution of sodium ethoxide (170 mg,
2.6 mmol) in ethanol (1 cm3). The mixture became homogenous
then a white precipitate formed which was diluted with a further
portion of ethanol (10 cm3). The resulting suspension was boiled
for 30 min and then cooled to room temperature. The precipitate
was collected by filtration and dried under high vacuum (0.1 mm
Hg) which gave the crude disodium salt (491 mg, 1.05 mmol, 89%)
a white papery solid.
2.2 mmol) was added to the now homogeneous solution. The
reaction was stirred at 80 ◦C for 5 days and at the completion
of this period was cooled to room temperature and quenched
by addition of water (15 cm3). The volatiles were removed under
reduced pressure (0.5 mm Hg) and the residue was dissolved in
dichloromethane (25 cm3). The organic layer was washed with
water (15 cm3) then brine (15 cm3) and dried (Na2SO4), filtered
and evaporated. The resulting yellow oil was dissolved in ethanol
(8 cm3) and heated to reflux for 2 h. Slow crystallisation from
this solution over several days gave the title macrocycle as a white
microcrystalline solid (784 mg, 1.3 mmol, 60%). An analytically
pure sample was obtained by recrystallisation from CHCl◦3–MeOH
which gave microcrystalline white pellets; mp 203–205 C (lit.18d
The above disodium salt (491 mg, 1.05 mmol) was suspended
in anhydrous DMF (7 cm3) under a nitrogen atmosphere and
heated to 100 ◦C. To this suspension was added a solution of
2-[[(4-methylphenyl)sulfonyl](3-{[(4-methylphenyl)sulfonyl]oxy}-
◦
propyl)amino]ethyl-4-methylbenzenesulfonate
5
(719 mg,
193–194 C). Found: C, 55.3; H, 5.8; N, 6.8; S, 15.6%; MH+
1.27 mmol) in DMF (3.5 cm3) over a 4 h period. The resulting
solution was stirred at 100 ◦C for 7 days, whereupon, the volatiles
were removed (0.1 mm Hg). The residue was partitioned between
dichloromethane (10 cm3) and dilute hydrochloric acid (0.23 M,
13 cm3) and the layers were separated. The aqueous phase was
extracted with dichloromethane (2 × 10 cm3) and the combined
organic layers were dried (Na2SO4), filtered and evaporated to
afford an oil. This oil was dissolved in ethanol (10 cm3) under a
nitrogen atmosphere and this solution was heated under reflux for
2 h to afford a white solid. Filtration afforded the title macrocycle
( )-3 as a white microcrystalline solid (153 mg, 0.24 mmol, 23%).
The physical and spectroscopic properties were identical to those
reported above.
606.1766. C28H35N3O6S3 requires: C, 55.5; H, 5.8; N, 6.9; S, 15.9%;
MH+ 606.1766. mmax (KBr, cm−1) 3029 (w, C6H4), 2928 (w, CH),
1339 (s, SO2NH), 1158 (s, SO2NH), 816 (w, C6H4); dH (400 MHz,
CDCl3) 0.78 (d, J 5.2 Hz, 3H, CH3CH), 2.43 (s, 9H, 3 × C6H4CH3),
3.09–3.19 (m, 3H, CH2), 3.31–3.39 (m, 3H, CH2), 3.49–3.53 (m,
1H, CH2), 3.62–3.68 (m, 3H, CH2), 4.40–4.53 (m, 1H, CH2CH),
7.29–7.37 (m, 6H, C6H4CH3), 7.62 (d, J 8.4, 2H, C6H4CH3),
7.75 (d, J 8.0, 2H, C6H4CH3), 7.78 (d, J 8.4, 2H, C6H4CH3);
dC (100 MHz, CDCl3) 14.6 (CH3CH), 21.7 (3 × C6H4CH3), 45.8
(NCH2), 50.8 (NCH2), 53.3 (NCH2), 54.0 (NCH2), 54.3 (NCH2),
55.3 (NCH), 127.5 (2 × C6H4CH3), 127.6 (2 × C6H4CH3), 127.8
(2 × C6H4CH3), 130.0 (4 × C6H4CH3), 130.1 (2 × C6H4CH3),
134.5, 135.2, 136.8 (all ArC), 143.8 (2 × ArC), 144.3 (ArC).
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1,4,7-Tris[(4-methylphenyl)sulfonyl]-1,4,7-triazacyclononane
17b.
( )-1,7-Bis[(4-methylphenyl)sulfonyl]-4-[(4-nitrophenyl)-
sulfonyl]dodecahydro-1H-1,4,7-benzotriazonine 19.
Method E (lithium hydride in DMF) (Table 1, entry 11).
The title compound 19 was prepared in a similar manner to
17b via method E using ( )-4-methyl-N-(2-{[(4-methylphenyl)-
Method E (lithium hydride in DMF) (Table 1, entry 7). To
a stirred suspension of lithium hydride (33 mg, 4.18 mmol)
in anhydrous DMF (15 cm3) was added 4-methyl-N-(2-
{[(4-methylphenyl)sulfonyl]amino}ethyl)benzenesulfonamide 16b
(731 mg, 1.98 mmol) under a nitrogen atmosphere. The resulting
mixture was heated to 70 ◦C for 2 h, whereupon, it was cooled to
sulfonyl]amino}cyclohexyl)benzenesulfonamide
4
(306 mg,
0.72 mmol) and 2-[[(4-nitrophenyl)sulfonyl](2-{[(4-nitrophenyl)-
sulfonyl]oxy}ethyl)amino]ethyl 3-nitrobenzenesulfonate 18
◦
(521 mg, 0.79 mmol) which afforded the title compound 19 as
a white solid (279 mg, 0.41 mmol, 57%). An analytical sample
was obtained by column chromatography using alumina (grade
III) using dichloromethane as the eluant which gave a white
microcrystalline solid; mp 262–264 ◦C. Found: C, 53.5; H, 5.4;
N, 7.9%; MH+677.1767. Calculated for C30H36N4O8S3: C, 53.2;
H, 5.4; N, 8.3%; MH+ 677.1773. mmax (KBr, cm−1) 2930 (w, CH),
1599 (w, Ar), 1531 (s, ArNO2), 1352 (s, ArNO2), 1331 (s, SO2NH),
1158 (s, SO2NH); dH (400 MHz, CDCl3) 1.09–1.19 (m, 2H, CH2),
1.21–1.42 (m, 3H, CH2), 1.52–1.56 (m, 1H, CH2), 1.72–1.80
(m, 1H, CH2), 2.04–2.14 (m, 1H, CH2), 2.39 (s, 3H, C6H4CH3),
2.42 (s, 3H, C6H4CH3), 2.73–2.85 (m, 1H, CH2NTs), 3.18–3.35
(m, 4H, CH2NTs), 3.44–3.59 (m, 3H, CH2NTs 3.72–3.75 (m,
1H, CHNTs), 4.79–4.80 (m, 1H, CHNTs), 7.23–7.36 (m, 4H,
C6H4SO2), 7.23–7.36 (m, 4H, C6H4CH3), 7.75 (d, J 6.0 Hz,
2H, C6H4SO2), 7.92–8.01 (m, 2H, C6H4SO2) 7.91 (d, J 8.4, 2H,
C6H4SO2), 8.29 (d, J 8.4, 2H, C6H4NO2); dC (100 MHz, CDCl3)
21.6 (2 × C6H4CH3), 24.6 (CH2) 26.0 (CH2), 28.9 (CH2), 30.2
(CH2), 46.9 (NCH2), 52.5 (NCH2), 55.4 (NCH2), 55.7 (NCH2),
60.3 (NCH), 68.2 (NCH), 124.7 (4 × C6H4SO2), 127.7 (C6H4SO2),
128.5 (C6H4SO2) 128.6 (4 × C6H4SO2), 129.7 (C6H4SO2), 129.9
(C6H4SO2), 137.2 (ArC), 138.2 (ArC), 143.4 (2 × ArC), 143.8
(ArC), 150.4 (ArC).
50 C. A solution of 2-[[(4-methylphenyl)sulfonyl](3-{[(4-methyl-
phenyl)sulfonyl]oxy}propyl)amino]ethyl-4-methylbenzenesulfo-
nate 5 (1.24 g, 2.18 mmol) in DMF (3.6 cm3) was added dropwise
over a 2.5 h period. The reaction mixture was maintained at 50 ◦C
for 5 days, whereupon, it was cooled to room temperature. Water
(5 cm3) was added and the volatiles were removed in vacuo (0.5 mm
Hg). The resulting residue was dissolved in dichloromethane
(25 cm3). and washed with water (15 cm3) then brine (15 cm3)
and dried (Na2SO4), filtered and evaporated. The resulting oil was
suspended in ethanol (15 cm3) and heated to reflux for 2 h under
a nitrogen atmosphere which afforded the title compound 17b as
a white solid (1.07 g, 1.8 mmol, 91%). An analytical sample was
obtained by recrystallisation from CHCl3–MeOH which gave fine
white needles; mp 222–223 ◦C (lit.24 218–220 ◦C). Found: C, 54.5;
H, 5.6, N, 7.0; S, 16.0%; MH+ 592.1609. C27H33N3O6S3 requires:
C, 54.8; H, 5.6; N, 7.1; S, 16.3%; MH+ 592.1609. mmax (KBr, cm−1)
2927 (w, CH), 1336 (s, SO2NH), 1322 (m), 1161 (s, SO2NH), 817
(w, C6H4); dH (400 MHz, CDCl3) 2.41 (s, 9H, 3 × C6H4CH3), 3.46
(s, 12H, 6 × NCH2), 7.31 (d, J 8.0 Hz, 6H, C6H4CH3), 7.69 (d, J
8.0, 6H, C6H4CH3); dC (100 MHz, CDCl3), 21.7 (3 × C6H4CH3),
52.0 (6 × NCH2), 127.6 (6 × C6H4CH3), 130.0 (6 × C6H4CH3),
134.8 (3 × ArC), 144.0 (3 × ArC).
(7aR,11aR)-1,4,7-Tris[(4-methylphenyl)sulfonyl]dodecahydro-
1H-1,4,7-benzotriazonine 3.
Deprotection and N-methylation
Method E (lithium hydride in DMF) (Table 1, entry 10).
The title compound (1R,2R)-3 was prepared in a similar man-
ner to 17b via method E using (1R,2R)-4-methyl-N-(2-{[(4-
(7aR,11aR)-Dodecahydro-1H-1,4,7-benzotriazonine trihydro-
chloride 20. To
a solution of 1,4,7-tris[(4-methylphenyl)-
sulfonyl]dodecahydro-1H-1,4,7-benzotriazonine (R,R)-3 (1.00 g,
1.5 mmol) in THF (25 cm3) and EtOH (4.8 cm3, 84 mmol) was
condensed dry NH3 (200 cm3) at −78 ◦C. To this solution was
added lithium metal (542 mg, 77 mmol) in small portions to
give an intense blue colour. The reaction mixture was allowed to
warm to room temperature overnight. Water was added (10 cm3)
and the solution was acidified (pH 1) with conc. HCl (1 cm3).
The aqueous solution was extracted with dichloromethane (×2,
10 cm3). The aqueous phase was made basic (pH 14) by addition
of solid NaOH (ca. 500 mg). The basic solution was extracted
with dichloromethane (×4, 10 cm3) and the combined organic
phases were dried (Na2SO4), filtered and evaporated to give a
crude dark yellow oil (310 mg). The yellow oil was dissolved in
methanol (2 cm3) and conc. HCl (0.08 cm3) was added dropwise
at room temperature with rapid stirring. To this solution was
added diethyl ether (8 cm3) and the white precipitate that formed
was removed by filtration and dried under reduced pressure to
give the crude hydrochloride salt (297 mg, 1.1 mmol, 73%); mp
methylphenyl)sulfonyl]amino}cyclohexyl)benzenesulfonamide
4
(2.70 g, 6.4 mmol) and 2-[[(4-methylphenyl)sulfonyl](3-{[(4-
methylphenyl)sulfonyl] oxy}propyl)amino]ethyl-4-methylbenzene-
sulfonate 5 (4.00 g, 7 mmol) which afforded the title◦macrocycle as
a white solid (2.81 g, 0.25 mmol, 68%); mp 301–302 C (lit.19c 294–
295 ◦C); Found: C, 57.7; H, 6.1; N, 6.5; S, 14.9%; MH+ 646.2086.
C31H39O6S3N3 requires: C, 57.7; H, 6.1; N, 6.5; S, 14.9%; MH+
646.2079; [a]D = −63.4 (c = 1, CHCl3) [lit.19c [a]D = −53.9 (c = 1,
CH2Cl2)]. mmax (KBr, cm−1) 3065 (w, C6H4), 2928 (m, CH), 2865 (m,
CH), 1326 (s, SO2NH), 1153 (s, SO2NH); dH (400 MHz, CDCl3)
1.11 (m, 2H, CH2), 1.26 (m, 2H, CH2), 1.56 (m, 2H, CH2), 1.76 (m,
1H, CH2), 2.16 (m, 1H, CH2), 2.35 (s, 3H, C6H4CH3), 2.41 (s, 6H,
C6H4CH3), 2.59 (m, 1H, CH2NTs), 3.11 (m, 1H, CH2NTs), 3.27
(m, 3H, CH2NTs), 3.49 (m, 3H, CH2NTs), 3.75 (m, 1H, CHNTs),
4.89 (m, 1H, CHNTs), 7.29 (m, 6H, C6H4CH3), 7.61 (d, J 8.3 Hz,
2H, C6H4CH3), 7.76 (m, 2H, C6H4CH3), 8.00 (m, 2H, C6H4CH3);
dC (100 MHz, CDCl3) 21.7 (3 × C6H4CH3), 24.7 (CH2), 26.1
(CH2), 29.0 (CH2), 30.3 (CH2), 47.1 (CH2NTs), 52.4 (CH2NTs),
55.0 (CH2NTs), 55.8 (CH2NTs), 60.2 (CHNTs), 68.2 (CHNTs),
127.3 (2 × ArCH), 127.9 (2 × ArCH), 128.7 (2 × ArCH), 129.7
(2 × ArCH), 129.9 (4 × ArCH), 130.1 (2 × ArC), 135.1 (ArC),
137.5 (ArC), 143.6 (ArC), 144.2 (ArC).
◦
176–178 C (lit.19c 240 ◦C (decomp.). Found: C, 40.6; H, 8.6;
N, 13.1%; (MH − 3HCl)+ 184.1815. C10H21N3·MeOH requires:
C, 40.7; H, 8.7; N, 12.9%; (MH − 3HCl)+ 184.1813; [a]D −122
(c = 0.135, H2O) (lit.19c [a]D = −55.6 (c = 0.4, H2O). mmax
(KBr, cm−1) 3419 (w, NH); 2943 (s, CH), 2862 (s, CH), 2778
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(s, CH); dH (400 MHz, D2O) 1.31 (m, 2H, CH2), 1.50 (m, 2H, CH2),
1.82 (m, 2H, CH2), 2.10 (m, 2H, CH2), 3.13 (m, 2H, NHCH2), 3.31
(m, 6H, NHCH2), 3.41 (m, 2H, NHCH); dC (100 MHz, CD3OD)
24.3 (2 × CH2), 29.7 (2 × CH2), 39.7 (2 × NHCH2), 43.2 (2 ×
NHCH2), 57.7 (2 × NHCH).
added and the reaction mixture was stirred for 72 h. The resulting
mixture was filtered through alumina using ethyl acetate as the elu-
ant. Evaporation of the solvent and recrystallisation from diethyl
ether–hexane at −20 C afforded 1-[(4-methylphenyl)sulfonyl]-2-
◦
phenylaziridine 25 as an ◦off-white solid (40 mg, 0.15 mmol, 49%)
mp 86–88 ◦C (lit.17 88–90 C). Found: MH+ 274.0903. C15H15NO2S
requires:MH+ 274.0902. mmax (KBr, cm−1) 3359 (w, NHTs), 3042
(m, NH), 2977 (w, CH), 1316 (s, SO2NH), 1154 (s, SO2NH); dH
(400 MHz, CDCl3) 2.43 (d, J 4.5 Hz, 1H, CHH), 2,47 (s, 3H,
C6H4CH3), 3.02 (d, J 7.2, 1H, CHH), 3.82 (dd, J 7.2, 4.5, 1H,
CHPh), 7.25–7.38 (m, 7H, ArCH), 7.91 (d, J 8.3, 2H, C6H4); dC
(100 MHz, CDCl3) 21.9 (C6H4CH3) 36.1 (CH2), 41.3 (CH), 126.8
(2 × ArCH), 128.2 (2 × ArCH), 128.5 (ArC), 128.8 (ArCH), 130.0
(2 × ArCH), 135.3 (ArC), 144.8 (ArC). Chiral HPLC indicated
that the two enatiomeric products were formed in a 1 : 1 ratio; tR =
11.45 min and 13.98 min
(7aR,11aR)-1,4,7-Trimethyldodecahydro-1H -1,4,7-benzotri-
azonine 1. (7aR,11aR)-Dodecahydro-1H-1,4,7-benzotriazonine
trihydrochloride (R,R)-20 (305 mg, 1.04 mmol) was dissolved in
water (20 cm3) and the solution was made basic (pH 14) by the
addition of solid NaOH (ca. 250 mg). The basic solution was
extracted with dichloromethane (×4, 10 cm3) and the combined
organic phases were dried (Na2SO4), filtered and evaporated to
give a pale yellow oil. To this oil was added formaldehyde (38%,
0.8 cm3) and formic acid (90%, 0.9 cm3) and the solution was
heated to reflux (bath temp. 90 ◦C) under a nitrogen atmosphere for
20 h. After cooling to room temperature the reaction was acidified
(pH 1) with conc. HCl (1 cm3) and the volatiles were removed
under reduced pressure. The aqueous solution was extracted with
dichloromethane (×2, 10 cm3). The aqueous phase was made basic
(pH 14) by addition of solid NaOH (ca. 250 mg). The basic
solution was extracted with dichloromethane (×4, 10 cm3), and
the combined organic phases were dried (Na2SO4), filtered and
evaporated to give a pale yellow oil (185 mg, 0.82 mmol, 79%).
Found: MH+ 226.2280. Calculated for C13H27N3 MH+: 226.2283;
[a]D −48.8 (c = 0.5, CHCl3). mmax (liq. film, cm−1) 2933 (m, CH),
2857 (m, CH), 2791 (m, CH), 1666 (s), 1451 (s, CH), 732 (s, CH2);
dH (400 MHz, CDCl3) 1.05 (m, 4H, CH2), 1.63 (m, 2H, CH2), 1.73
(m, 2H, CH2), 2.29 (s, 9H, NCH3), 2.48 (m, 6H, NCH2), 2.60 (m,
2H, NCH2) 2.95 (m, 2H, NCH); dC (100 MHz, CDCl3) 25.2 (2×
CH2), 27.0 (2× CH2), 40.2 (2 × NCH3), 46.8 (NCH3), 54.4 (2×
NCH2), 54.8 (2× NCH2), 63.6 (2 × NCH).
Acknowledgements
This work was funded under the Adventurous Chemistry award
EP/C532309/1 which funded R. T. We also thank the EPSRC for
a studentship (to G. S.). We are also grateful (K. R.-D.) for funding
from the ERASMUS association and the region Rhoˆne-Alpes. We
also thank Raghu R. Morthala for recording a number of spectra.
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Copper(II) complex formation
To a solution of copper(II) chloride (162 mg, 1.2 mmol) in
anhydrous acetonitrile (20 cm3) under a nitrogen atmosphere was
added a solution of (7aR,11aR)-1,4,7-trimethyldodecahydro-1H-
1,4,7-benzotriazonine 1 (271 mg, 1.2 mmol) in acetonitrile (5 cm3).
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(m, CH), 2859 (w, CH), 1705 (s), 1690 (s), 1422 (s), 1204 (s), 1180
(s), 1126 (s), 723 (s); kmax [CH3CN, nm (e)] 284 (4806), 548 (28),
652 (88).
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