Azetidines as intermediates in polyamine synthesis - Structure and reactions of a quadridentate ligand incorporating an azetidine ring

Article abstract of DOI:10.1039/b200382a

Reaction of the tris(benzene sulfonate) of 1,1,1-tris-(hydroxymethyl)ethane with neat 1,2-ethanediamine under relatively mild conditions leads to formation in good yield (60%) of a quadridentate amine incorporating a four-membered, azetidine ring, the nature of the tetramine being established by determination of the crystal structures of two of its cobalt(III) complexes and the reactivity of the azetidine ring being explored in further reactions with 1,2-ethanediamine.

Full text of DOI:10.1039/b200382a

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Azetidines as intermediates in polyamine synthesis – structure and
reactions of a quadridentate ligand incorporating an azetidine ring
a
b
b
c
d
Jack M. Harrowfield,* Gyu Hwan Jang, Yang Kim, Pierre Thuéry and Jacques Vicens
a
Department of Chemistry, University of Western Australia, 35 Stirling Highway,
Crawley WA 6009, Australia
Department of Chemistry, Kosin University, Yeongdo-gu, Pusan 606-701, Korea
CEA/Saclay, SCM (CNRS URA 331), Bât. 125, F-91191 Gif-sur-Yvette, France
ECPM, Université Louis Pasteur de Strasbourg, 25, rue Becquerel,
b
c
d
F-67087 Strasbourg Cédex 2, France
Received 11th January 2002, Accepted 18th February 2002
First published as an Advance Article on the web 27th February 2002
Reaction of the tris(benzene sulfonate) of 1,1,1-tris-
(
hydroxymethyl)ethane with neat 1,2-ethanediamine under
relatively mild conditions leads to formation in good yield
60%) of a quadridentate amine incorporating a four-
(
membered, azetidine ring, the nature of the tetramine
being established by determination of the crystal structures
of two of its cobalt(III) complexes and the reactivity of
the azetidine ring being explored in further reactions with
1
,2-ethanediamine.
In the synthesis of elaborate polyamine ligands by the reaction
1,2
of simpler polyamines with polyalkylating agents, it is com-
mon to observe products arising from cyclisation processes,
even despite the use of the neat amine as solvent in order to
maximise the rates of intermolecular reactions competing with
intramolecular cyclisation. Specifically, in comparing reactions
2
involving 1,2- vs. 1,3-diamines, it is found that cyclisation is far
more prominent with the former than the latter, a result which
may be rationalised as a result of the higher rates of formation
of smaller rings (relative to further intermolecular substitution
processes). Most of these cases, however, concern only 6- vs.
7
- or 7- vs. 8-membered rings, despite the facts that formation
Fig. 1 Possible pathways in the reaction between 1,1,1-tris(hydroxy-
of smaller rings would, at least in some instances, appear
possible and, in particular, that there are reasons to expect
similar rates for formation of 4- and 7-membered rings.
methyl)ethane derivatives and 1,2-ethanediamine.
3
materials, we have now structurally confirmed that an azetidine
derivative is formed during the synthesis of sen.
The reaction of various electrophilic derivatives of 1,1,1-
tris(hydroxymethyl)ethane with 1,2-ethanediamine has long
been known as a pathway to the sexidentate amine, “sen” (1,
Following reaction of 1,1,1-tris(benzenesulfonyloxy)ethane
in neat 1,2-ethanediamine at 90 ЊC for 72 h,† the bulk of the
excess diamine was removed by distillation under reduced
pressure and the ligands present were then separated by the
formation and ion-exchange chromatography of their Co()
complexes. The bulk product (60% yield) proved to be a green
complex that, following its conversion to the slightly
soluble perchlorate salt, 4, was characterised by an X-ray, crys-
tal structure determination (Fig. 2(a)).‡ The structure confirms
the presence of the azetidine ring as in 3, with the dimensions
of the Co() coordination environment being generally
1,4–6
6
Fig. 1),
with a side product of the reaction being identified
as the (2Ј-aminoethylamino)methyl-functionalised derivative of
the diazepam resulting from both nitrogen atoms of a diamine
molecule reacting with separate alkylating sites (2, Fig. 1). The
two ligands can be easily distinguished by formation of their
complexes with cobalt() chloride, since the hexamine gives a
yellow, tripositive complex ion involving a CoN coordination
unit while the tetramine gives a purple, unipositive cation
6
involving a cis-CoN Cl2 unit (though under preparative
4
6
8
conditions, 2 has commonly been isolated as the yellow
unremarkable, the longest Co–N bond being that to the
3ϩ
[Co(2)en] species). In attempting to conduct syntheses of long
tertiary azetidine N, though the elongation is relatively small
compared to that observed for tertiary donors in cage amine
7
chain analogues of sen, however, we observed on several occa-
sions the formation of a ligand which gave a green Co() com-
plex, this colour indicating it to be a trans-CoN Cl species.
9
systems. The azetidine ring itself shows appreciable distortions
10
of the geometry of the simple heterocycle but is little different
4
2
11
Since the diazepam derivative could not provide a planar
array of its 4 N-donors about Co(), it was speculated at the
time that the ligand present may have been the homologue of
the azetidine derivative 3 (Fig. 1), for which such a coordination
geometry would appear possible. This remained uncertain,
however, as it has been reported that 1 (sen) will in fact provide
a green Co() species, involving only partial coordination of
the ligand, under certain preparative conditions. Though
crystals suitable for confirmation of the structure by X-ray dif-
fraction could not be obtained from these earlier green
from that of azetidinium species or that of the azetidine ring
12
in a very closely related Co() complex. Its presence in the
quadridentate ligand renders it, once coordination stabilises the
secondary nitrogen atom to inversion, a resolvable chiral ligand
of the “232 tet” type, the space group (P2 2 2 ) indicating 4 to
1
1 1
crystallise as a “racemic mixture”, with the particular crystal
taken for the structure solution being one in which the chiral
coordinated nitrogen atom has the R configuration and the two
5-membered chelate rings have the δ conformation, as shown in
Fig. 2(a).
1
DOI: 10.1039/b200382a
J. Chem. Soc., Dalton Trans., 2002, 1241–1243
This journal is © The Royal Society of Chemistry 2002
1241

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been reported not to undergo nucleophilic ring-opening
reactions with diamines. Since azetidine ring opening by
14
ammonia does appear to occur under forcing conditions,
it is clearly a reaction which is sensitive to minor structural
variations in the reactants, perhaps owing to differences in ring
strain.
Acknowledgements
This work was partly supported by Kosin University.
Notes and references
†
0
Synthesis and isolation: 1,1,1-tris(benzenesulfonyloxy)ethane (54 g,
.1 mol) and 1,2-ethanediamine (en; 300 mL) were heated under a
nitrogen atmosphere at 90 ЊC for 72 h. After cooling, excess diamine
was distilled out under reduced pressure, a solution of NaOH (12.3 g,
0
.31 mol) in methanol (150 mL) added, and sodium benzenesulfonate
then filtered off. Cobalt chloride (32 g, 0.13 mol) in methanol (300 mL)
and glacial acetic acid (12 g) were added to the filtrate, and the mixture
was aerated for 10 h. After adding concentrated HCl (35 mL), the
solvents were removed under reduced pressure and the residue dissolved
in water (1 L). Chromatography on Dowex 50W × 2 cation exchange
Ϫ1
resin using 2 mol L HCl as eluant revealed 4 components, F1, F2, F3
2
ϩ
3ϩ
and F4. Pink F1 was Co , orange F3 was largely [Co(en)3] and green
F4 contained too little material for it to be conveniently isolated. The
eluate containing the major, green product F2 was evaporated down to
a volume of 50 mL before NaClO was added to precipitate the com-
4
plex 4 (yield, 25 g, 60%). It was recrystallised by slow cooling of its
solution in hot, dilute HCl.
A solution of 4 and excess en in DMSO was heated at 60 ЊC for
6
0 min. Cation exchange chromatography of the orange product
3ϩ 3ϩ
mixture provided [Co(en)3] and [Co(3)en] as the only materials
present in significant amounts. The latter was isolated as its chloride
(
trihydrate) 5, which was recrystallised from dilute HCl by vapour
Fig. 2 (a) View of the Co() cation present in 4, ellipsoids drawn at
the 60% probability level; counter ion omitted for clarity. Selected bond
lengths (Å) and angles (Њ): Co–N1 1.975(2), Co–N2 1.990(2), Co–N3
diffusion of ethanol.
1
The 200 MHz H NMR spectra (D O solvent) of the diamagnetic
2
complexes 4 and 5 were complicated, as expected from the low
symmetry of the complexes, but both showed multiplets, δ 3.5–3.7,
attributable to two superimposed AB system methylene resonances of
the azetidine ring. Reduction of 4 to its labile Co() form by addition
of NaBH to its solution in dilute HCl allowed isolation of the hydro-
chloride of 3 via ion exchange chromatography.
1
.957(2), Co–N4 1.954(2), Co–Cl1 2.2558(7), Co–Cl2 2.2614(8); N1–
Co–N2 86.48(9), N2–Co–N3 89.11(9), N3–Co–N4 86.48(10), N4–Co–
N1 97.93(10), Cl1–Co–Cl2 171.20(3). (b) View of the Co() cation
present in 5, chloride counter ions and water molecules of hydration
omitted, ellipsoids drawn at the 60% probability level. Selected bond
lengths (Å) and angles (Њ): Co–N1 1.953(6), Co–N2 1.989(6), Co–N3
4
‡
X-Ray crystallography: data were collected on a Nonius-Kappa-CCD
2
.004(6), Co–N4 1.984(6), Co–N5 1.983(6), Co–N6 1.992(6); N1–Co–
N2 85.9(2), N1–Co–N4 88.0(2), N1–Co–N5 91.4(2), N1–Co–N6
1.0(3), N2–Co–N3 91.7(2), N2–Co–N4 96.6(2), N2–Co–N6 89.7(2),
area detector diffractometer using graphite-monochromated Mo-Kα
1
7
radiation (λ = 0.7107 Å), and were processed with DENZO-SMN.
The structures were solved by direct methods with SHELXS-97 and
subsequent Fourier-difference synthesis, and refined by full-matrix
least-squares on F with SHELXL-97. Absorption effects were
9
3
1
8
N3–Co–N4 84.3(2), N3–Co–N5 92.0(2), N3–Co–N6 97.1(2), N4–Co–
N5 90.7(2), N5–CoN6 82.9(2).
2
19
2
0
empirically corrected with the program DELABS from PLATON.
All non-hydrogen atoms have been refined with anisotropic displace-
ment parameters. The absolute structure of 4 was determined from the
The coordination chemistry of azetidine has been little
12–15
explored
but it is known in the case of its more widely
2
1
value of Flack’s parameter, Ϫ0.010(14). The hydrogen atoms bound to
nitrogen atoms have been found on the Fourier-difference map, whereas
all other hydrogen atoms were introduced at calculated positions except
those of the water molecules in 5. All of them have been treated as
riding atoms with an isotropic displacement factor equal to 1.2 (NH,
NH , CH ) or 1.5 (CH ) times that of the parent atom. The molecular
studied homologue, aziridine, that metal ion coordination can
16
stabilise a strained ring towards nucleophilic ring opening.
Thus, it is not surprising to find that whereas the complex 4
reacts with 1,2-ethanediamine to give a reddish-yellow species
3ϩ
[
Co(3)en] (isolated and structurally characterised (Fig. 2(b))
2
2
3
2
2
as the chloride 5) in which the azetidine ring is retained and
plots were drawn using SHELXTL, all calculations being performed
the ligand is bound as a quadridentate with the secondary
on a Silicon Graphics R5000 workstation. Crystal data for 4:
C H Cl CoN O , M = 415.59, orthorhombic, space group P2 2 2 , a =
(
asymmetric) nitrogen donor rather than the tertiary occupying
9
22
3
4
4
1 1 1
3
9
.3136(8), b = 12.2253(10), c = 14.0044(6) Å; V = 1594.6(2) Å , Z = 4;
the “angular” site, extended heating of the reaction mixture
from which 3 is isolable at a higher temperature (120 ЊC) led to
the complete loss of 3 and the detection of 1 and 2 only in the
product mixture. These results imply that 3 may be an inter-
mediate in the formation of sen from the original trisulfonate
and, given the yield of 3 obtained under the conditions
Ϫ3
Ϫ1
D = 1.731 g cm , F(000) = 856, µMo = 1.598 mm , T = 100(2) K, 2667
c
observed reflections [I > 2σ(I )] out of 2800 unique reflections collected
[
Rint = 0.051], 191 parameters, R1 = 0.026 [I > 2σ(I )], wR = 0.061
2
Ϫ3
(
all data), S = 1.020, ∆ρmax = 0.214 e Å . For 5: C H Cl CoN O ,
11 36 3 6 3
¯
M = 465.74, triclinic, space group P1, a = 7.9455(6), b = 8.2960(7),
c = 16.7784(11) Å; α = 101.991(4), β = 94.963(4), γ = 110.356(4)Њ; V =
3
Ϫ3
Ϫ1
described herein, that the pathway 3
1 must in fact be the
999.0(1) Å , Z = 2; D = 1.548 g cm , F(000) = 492, µMo = 1.283 mm ,
c
dominant route. A plausible rationalisation of what now is
known of these ligand syntheses is that the initial step of the
reaction must involve the displacement of two sulfonate groups
by one nitrogen atom of an ethanediamine molecule. This
would give an azetidine ring which could subsequently undergo
ring expansion (giving 2) by intramolecular reaction with a
pendent amine group or an intermolecular ring opening by
ethanediamine (to give 1). The azetidine formation would
appear to parallel that in the formation of some very closely
T = 100(2) K, 2639 observed reflections [I > 2σ(I )] out of 3290 unique
reflections collected [Rint = 0.061], 219 parameters, R1 = 0.079 [I >
Ϫ3
2
σ(I )], wR = 0.176 (all data), S = 1.008, ∆ρ
= 0.863 e Å . CCDC
2
max
reference numbers 177443 and 177444. See http://www.rsc.org/
suppdata/dt/b2/b200382a/ for crystallographic data in CIF or other
electronic format.
1
R. W. Green, K. W. Catchpole, A. T. Philip and F. Lions, Inorg.
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12
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1
242 J. Chem. Soc., Dalton Trans., 2002, 1241–1243

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3
4
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6
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7
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5
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1
1
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J. Chem. Soc., Dalton Trans., 2002, 1241–1243
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