Conformational analysis and synthetic approaches to polydentate perhydro-diazepine ligands for the complexation of gallium(iii)

Article abstract of DOI:10.1039/c3ob40287h

Synthetic approaches are reported to polydentate ligands based on 6-phenyl-6-amino-perhydro-1,4-diazepine. The synthetic route devised averts ring-opening reactions, allowing the exocyclic N-substituent to be introduced separately and involves a nitro-Mannich condensation, prior to chemoselective RANEY nickel reduction. Comparison of the solid-state structures of four synthetic intermediates reveals that the seven-membered ring adopts a preferred twist-chair conformer in the solid state. Solution state NMR experiments highlight a conformational preference for the bulky aryl groups to adopt an equatorial site, pre-disposing the ligand to metal binding, by adoption of a conformation that creates a facial array of the ligand nitrogen atoms. This ligand conformation averts the formation of less stable metal complexes with differing ligation modes, notably in the binding of Ga³⁺ to related ligands, where a C-methyl substituent replaces the phenyl group at the quaternary centre.

Full text of DOI:10.1039/c3ob40287h

Organic &
Biomolecular Chemistry
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PAPER
Conformational analysis and synthetic approaches to
polydentate perhydro-diazepine ligands for the
complexation of gallium(III)†
Cite this: Org. Biomol. Chem., 2013, 11,
2827
David Parker* and Bradley P. Waldron
Synthetic approaches are reported to polydentate ligands based on 6-phenyl-6-amino-perhydro-1,4-di-
azepine. The synthetic route devised averts ring-opening reactions, allowing the exocyclic N-substituent
to be introduced separately and involves a nitro-Mannich condensation, prior to chemoselective
RANEY nickel reduction. Comparison of the solid-state structures of four synthetic intermediates
®
reveals that the seven-membered ring adopts a preferred twist-chair conformer in the solid state. Solu-
tion state NMR experiments highlight a conformational preference for the bulky aryl groups to adopt an
equatorial site, pre-disposing the ligand to metal binding, by adoption of a conformation that creates a
facial array of the ligand nitrogen atoms. This ligand conformation averts the formation of less stable
metal complexes with differing ligation modes, notably in the binding of Ga3+ to related ligands, where
a C-methyl substituent replaces the phenyl group at the quaternary centre.
Received 7th February 2013,
Accepted 6th March 2013
DOI: 10.1039/c3ob40287h
www.rsc.org/obc
premature metal dissociation in vivo has meant that macrocyc-
lic ligand systems have often been preferred, especially those
Introduction
Finding ligands that bind metal ions rapidly yet form kineti- that are sensibly matched in coordination number and donor
cally stable complexes for safe use in vivo remains a challen- type to the given metal ion and are pre-organised to the
ging task.1 Recently we have reported the behaviour of certain required coordination geometry. The hexadentate ligands
hexadentate ligands that bind 68Ga rapidly over the pH range NOTA4 1, and the triphosphinate analogues, 2,5,6 have there-
4–7 yet form kinetically stable complexes suitable for use in fore attracted attention for labelling with 67Ga(γ, 7.8 h), 68Ga
vivo.2 Here, we describe the details of the synthetic approach and 111In(γ, t1/2 68 h).7 These ions, like Fe3+, Co3+ and Zn2+
to such ligands, highlighting competitive ring-opening reac- prefer an octahedral coordination environment with ‘hard’
tions. In addition we assess their solution and solid-state con- donor atoms. The radiolabelled complexes resist acid catalysed
formations in detail, in order to explain their favourable dissociation in vivo8,9 but can be rather slow to label at
metal-ion binding characteristics.
ambient pH and temperature. The rate-limiting step in metal
Generally, acyclic systems possess fast forward rates of ion binding in aqueous media is likely to be associated with
metal binding, but are more susceptible to dissociation path- N-deprotonation of the ligand, a process which tends to be
ways. On the other hand, macrocyclic ligands usually form inhibited by the conformational rigidity of the 1,4,7-triaza-
more kinetically inert metal complexes but their higher cyclononane ligand, where there is a tendency to conserve the
binding stability constants are often associated with slower square [333] conformation. These issues are most acute with
rates of complexation and more particularly dissociation.3 68Ga labelling, owing to its short half-life and the propensity of
These issues are of particular importance in molecular the aqua ion to hydrolyse above pH 5.
imaging involving labelling of ligands by metallic radioiso-
The 7-ring heterocycle derivate 6-amino-6-methyl perhydro-
topes, especially with short-lived radionuclides, such as the 1,4-diazapine, 3a, is isomeric with 1,4,7-triazacyclononane, 4,
positron emitters 68Ga(t1/2 68 min), 64Cu(t1/2 12.8 h), 52Fe(t1/2 and like the unsubstituted analogue, 3b, (DAZA) it has
8.2 h) and 55Co(t1/2 17.5 h). The over-riding need to avoid attracted attention as a ligand scaffold, as N-substitution
readily allows formation of heptadentate and hexadentate
ligands.10–13 However, the conformational flexibility of satu-
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
rated,
heterocyclic
seven-membered
rings
is
well
E-mail: david.parker@durham.ac.uk
documented.14–17 Several low-energy conformations are popu-
lated, of which the twisted-chair (TC) conformations are
usually lowest in energy (Scheme 1). In addition, in 3a–3c, the
†Electronic supplementary information (ESI) available. CCDC 911245 and
911246. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ob40287h
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based on this scaffold that were more pre-organised towards
metal ion complexation, than ligands such as L5, L4a or L4b
(AAZTA)11 (Scheme 2). Furthermore, we needed to develop a
versatile synthetic route that allowed the exocyclic and endo-
cyclic N-substituents to be differentiated easily, thereby permit-
ting opportunities for selective conjugation via the exocyclic
nitrogen substituent.
Scheme 1
conformational equilibrium interconverts the axial and equa-
torial sites, with the more bulky 6-substituent preferring the
latter position.
Synthesis of ligands L1–L3
The key intermediate in the synthesis of L1–L3 proved to be the
nitro-compound 93 (Scheme 3). Prior work in the analogous
series of 6-methyl-substituted ligands had centred on a two-
step synthesis of 3a via co-condensation of nitromethane, for-
maldehyde and N,N-dibenzylethylenediamine, followed by
reductive hydrogenolysis using Pearlman’s catalyst.11a Such a
strategy was inappropriate here, as C-benzylic cleavage occurs
simultaneously, leading to ring-opening. Therefore, the acid-
labile 2,4-dimethoxybenzyl analogue was used, as it can be
In order for these ligands to present a facing-capping array
of three nitrogen donors, the 6-amino group needs to adopt an
axial position. This is preferred when the other 6-substituent
is more bulky. Consideration of literature ‘A’ values suggests
that an aryl ring at this site is preferred over a simple alkyl
+
group (Ph: 12 kJ mol−1; Me 7 kJ mol−1; NH2/NH3 6–7 kJ
mol−1; HN(CH2R)2 10 kJ mol−1) and can be readily derivatised
for subsequent conjugation. Accordingly, we set out to prepare
3c, and create hexadentate aza-carboxylate ligands, L1–L3,
Scheme 2
Scheme 3 Synthesis of L1.
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cleaved selectively by TFA under ambient conditions.18 The cleaved the electron rich benzyl groups and afforded the tri-
nitro-Mannich reaction was undertaken initially in aqueous amine 3c.
EtOH at 80 °C but under these conditions, solvolysis of the
This sequence of transformations from 5 was not high
product 5 also occurred at the benzylic site, leading to the yielding and an alternative route was explored that also
undesired tertiary alcohol, 6. At elevated temperatures and in allowed selective functionalisation of the exocyclic nitrogen.
this polar solvent, it is assumed that an SN1 reaction is Removal of the dimethoxybenzyl groups using TFA gave the
favoured. Such nitro/hydroxyl substitution reactions are rare diamine (9) followed by selective N-alkylation with an α-bromo-
t
but have previously been reported at tertiary nitroalkane acetate ester (R = Et or Bu). This process allowed the diesters
sites.19 By reducing both solvent polarity (50 : 50, PhMe–EtOH) 10 and 11 to be obtained in reasonable yield (Scheme 3). Sub-
and the reaction temperature (40 °C), this substitution reaction sequent nitro-reduction using hydrogenation over RANEY®
was suppressed, allowing the desired nitro-compound, 5 to be nickel generated the amines 12 and 13 which could by N-alkyl-
isolated in moderate yield.
ated again with the appropriate α-bromo ester to give the tri-
Reductive deprotection of 5 using tin, zinc or iron in HCl esters 14 and 15. Formation of the tetra-N-alkylated products
was compromised by concomitant solvolysis of the nitro- was inhibited by the steric bulk of the phenyl group and
group, and both direct or transfer (HCO2NH4 or N2H4) hydro- required more forcing conditions to give the tetra-ester, 10.
genolysis over various palladium on carbon catalysts failed to
Acidic deprotection (TFA/CH2Cl2) or aqueous base hydroly-
give the desired triamine 3c in significant yield. An attempt sis in THF of 14 or 15 gave rise to the target ligand L1. In the
was therefore made to employ the conditions used by Ganem case of the deprotection of 14, concomitant lactamisation of
−
for selective nitro-group reduction using NiB2/BH4 generated the product was observed – as had been noted earlier in the
in situ from NaBH4 and NiCl2.20 However, a reductive ring C-methyl series13,2 – but to a much lesser extent. Therefore,
opening reaction occurred instead, leading to exclusive for- the preferred sequence to L1 involves the use of ethyl bromoa-
mation of the N-methylated oxime, 7. The same product was cetate, as the base hydrolysis reaction conditions inhibit the
observed following reduction with LiAlH4 in Et2O. This undesired intramolecular cyclisation.
unusual reaction is presumably proceeding via a C-nitroso
The lactamisation reaction noted with L1 is impossible with
intermediate (Scheme 4), in which the endocyclic nitrogen a tertiary amine at the exocyclic site. Therefore, N-methylation
lone-pair is antiperiplanar to the cleaving carbon–carbon bond of 14 (MeI/MeCN) gave 17, followed by TFA treatment to offer
in a Grob fragmentation, assisted by the favourable σN–σ*CC the ligand L2, without any problems. Similarly, the use of (R)-
interaction. The successful selective reduction of the nitro ethyl-2-trifluoromethylsulfonyl-propionate
in
place
of
group in 5 was finally undertaken using hydrogenation over BrCH2CO2Et, in this sequence allowed the synthesis of (SSS)-L3
RANEY® nickel in ethanol at room temperature, as reported by to be undertaken via compounds 18, 19 and 20. In this case,
Go and co-workers.21 The monoamine was converted into the the lactamisation reaction does not occur at all when L3 is in
carbamate derivate 8 directly, to facilitate chromatographic acidic aqueous media.
purification. Subsequent treatment with TFA in CH2Cl2
The unexpected formation of the tertiary alcohol 6, via sol-
volysis of the nitro compound 5, permitted the synthesis of the
hexadentate ligand L6. In this compound, the alkoxy substitu-
ent may be estimated to have an ‘A’ value of about 2.5 kJ
mol−1, and hence the conformational bias in favour of the pre-
ferred geometry for metal ion binding is slightly greater than
with L1. Solvolysis of 5 in boiling aqueous ethanol afforded 6,
and following removal of the substituted N-benzyl groups
(TFA/CH2Cl2), the resultant diamine 21 was alkylated with tert-
butyl bromoacetate to afford the triester 22, as well as the
diester 23. Cleavage of the ester groups in 23 and 22 with TFA
led to formation of the pentadentate ligand, L7 and the hexa-
dentate compound L6 (Scheme 5). These are new ligand types
that will be the subject of further investigation in due course.
Conformational analysis of selected ligand intermediates
Earlier studies of the conformational analysis of 1,4-diazepine
derivative revealed a preference for a twisted-chair confor-
mer.14 In the case of 6-substituted derivatives, there are seven
such low energy conformations (Scheme 6). It is the presence
of unfavourable eclipsing interactions in the NCH2CH2N
moiety that disfavours population of alternative chair and boat
conformers (Scheme 1). Amongst the seven twist-chair (TCn)
conformers, one has the exocyclic N-substituent in an isoclinal
Scheme 4
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Scheme 5
(H33a3+),10 whilst in metal complexes of 3b and substituted
ligands derived from these triamines a chair conformation is
preferred as it allows a facial N3 array to be created, notwith-
standing the concomitant unfavourable eclipsing interaction
in the NCH2CH2N moiety10,11b,12,22,23 and the need to place
the N substituent in an axial site.
In the series of ligands defined herein, the metal-binding
conformation (Scheme 6) is in equilibrium with an alternate
chair, in which the N-substituent is equatorial. Exchange
between these high-energy conformers occurs via the preferred
TCn conformations, and the relative steric bulk of the C6 sub-
stituents in particular will determine the position of the equili-
brium and the energy barrier to conformer exchange.
Information concerning the ring conformation has been
obtained for selected ligand intermediates by crystallographic
analysis and by solution state 1H NMR nOe spectroscopy.
A set of three intermediates 10, 23 and 24, gave crystals suit-
able for X-ray analysis, and their structures were solved at
120 K and compared to that of compound 5.2 In each struc-
ture, the seven-membered ring adopts a twist-chair confor-
mation (Fig. 1). An alternate view taken along the C4–C5 bond
illustrates the isoclinal orientation of the substituents at the
quaternary centre. In each case, this corresponds to a TC4 con-
former (Scheme 6), and the compounds crystallised as a pair
of enantiomers, related via a puckering of the ring. The NCH2–
CH2N torsion angles were 56.9, 57.6, 54.7 and 49.3° for 5, 10,
23 and 24, respectively; such values are close to the ideal 60°
angle.
Scheme 6
Proton NMR NOESY experiments provided information
about the mutual spatial orientation of ligand protons in sol-
ution. In the ethyl esters 25 and 20, with C-Me and C-Ph
groups at the quaternary centre, the pairs of methylene
position (TC4) and two sets of three place it either axial (TC1–3
)
or equatorial (TC5–7). Crystal structures of the protonated salts
of 3a and 3b, reveal population of TC6 (H33b3+), and TC4/TC7
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Fig. 1 Views (from the left) of the intermediates 24, 5, 10 and 23 in the solid-
state (120 K): upper: showing the twist-chair conformation (TC4); centre: view
showing the isoclinal orientation of the substituents at the quaternary centre;
lower: illustrating the enantiomeric conformers for 5. Endocyclic N-substituents
and H-atoms are removed for clarity.
protons are diastereotopic and anisochronous. The NOESY
experiment allowed relative nOe enhancements to be assessed,
in each case (Fig. 2 and Table 1). Strong nOe correlations were
observed for 25, between the exocyclic NCH proton (labelled
Ha) and two endocyclic methylene protons, with a very weak
correlation between the quaternary C-Me groups (labelled Hb)
and this pair of protons. On the other hand, a very strong cor-
relation was observed between Hb and the other pair of
protons at C2 and C7 (Scheme 7). Thus, the methyl protons
have through-space interactions with an ‘axial’ orientated
proton on one carbon and an ‘equatorial’ proton on the other,
whilst for the NCHMe proton (quartet at 3.41 ppm) the other
pair of protons are close in space. Such correlations can tenta-
tively be rationalised in terms of the preferred population of a
TC4 conformer (Scheme 7). The nearest neighbour distances in
the X-ray analyses of 24 accord with this interpretation.
With the C-Ph triester, 20, fewer strong nOe correlations
were observed. NOE-correlations were found between the
ortho-phenyl protons, Hb and each proton at C2 and C7, but
only a weak nOe enhancement (4%) was measured between
the NCHMe proton and one H2 proton. Such behaviour is con-
sistent with the adoption of a major solution conformer in
which the exocyclic N-substituent adopts a more well-defined
‘axial’ position, with the phenyl ring equatorial and closer to
the plane of the heterocyclic ring. As a consequence, the
‘through space’ distance between the NCHMe proton and the
‘axial/equatorial’ proton pairs at C2 and C7 increases, as is
observed comparing relevant distances in the X-ray structures
of 24 and 5.
Fig. 2 2D-NOESY spectra (600 MHz, 298 K, CDCl3): upper, for 25 showing nOe
correlations between C-Me protons (Hb) and methylene hydrogens; lower, for
20 showing correlations between the C-Ph ortho hydrogens (Hb) and methylene
protons; centre, schematic showing the numbering system used.
Table 1 1H NMR NOESY correlations and relative enhancements observed for
25 and 20 (600 MHz, 298 K) between protons at C2 and C7 and the C-Me (Hb)
or C-Ph (ortho, Hb) protons, as well as the NCHMe proton (Ha)
Relative nOe
enhancement (%)
NOESY correlation
25
Hb–H2′
Hb–H7
Ha–H2
Ha–H7′
Hb–H2 and Hb–H7′
Hb–H2′ and Hb–H7′
Hb–H7
Hb–H2
Ha–H7′
39
27
21
11
≤2
31a,b
36
23
4
20
Comparative solution NMR behaviour of the protonated
ligands L4a and L1
a Note that there are two ortho phenyl hydrogens (Hb) rotating rapidly
about the C-Ph bond. b Signals were too close to separate individual
enhancements.
The sequence of protonation of the aza-carboxylate ligands L4a
(C-Me) and L1(C-Ph) has been assessed by following the
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Scheme 7
changes in the chemical shift of the 1H NMR ligand reson-
ances as a function of pH. Earlier work has shown that the
first pKa of L4a (and by inference L1) lies above pH 10.513b,2
and can be ascribed to protonation of the endocyclic nitrogen
to form a stable, bridged H-bond that rigidifies the structure.
The second protonation will then occur at the exocyclic nitro-
gen (Scheme 8). This protonation step may be accompanied by
a change in ligand conformation, as both Coulombic repulsion
and the increased steric demand of an N-protonated substitu-
ent dictate that the exocyclic N-substituent may prefer an equa-
torial site. The pKa value for H2L4a was measured to be 5.70
( 0.10) (295 K, I = 0.1 M NaCl)2 and parallel experiments with
H2L1 gave a value of 5.58 ( 0.10) (ESI†).
Proton NMR NOESY experiments were undertaken with
H2L4a at pH 2.0 (pD 2.4) 5.0 and pH 7. In the more acidic solu-
tion, the strongest nOe correlation was observed between the
quaternary methyl group and the 2 protons at C2/C7 resonating
to lower frequency (Fig. 3). The N–Me and proximate NCH2
groups showed a strong nOe correlation to the higher fre-
quency protons at C2/C7. In contrast, at pH 7, each of these
correlations was reversed and the C-Me group must then be
closer in space to the higher frequency protons, with the NMe
and NCH2C groups closer to the pair of protons resonating to
lower frequency. Such behaviour accords with a protonation
process in which the C-Me site occupies an axial site at lower
pH and the bulkier protonated N-substituent prefers to adopt
the equatorial position. At higher pH, these site preferences
are reversed. In contrast, parallel NOESY experiments with L1
in D2O showed no significant pH dependence of the nOe cor-
relations in the pH range 2 to 7, strongly suggesting that the
bulkier phenyl ring adopted the equatorial position constantly.
The behaviour of the protonated ligand [H2L4a]2+ at pD 2.4
was also examined by variable temperature 1H NMR spec-
troscopy. A series of spectra was recorded at 5 °C intervals
from 298 K to 363 K (ESI†). The endocyclic methylene protons
at C2 and C7 resonate as a simple AB spin system, separated by
Fig. 3 Partial 1H NMR spectra (700 MHz, 298 K) for the triester, 26 (CDCl3),
and for [H2L4a 2+
]
(D2O, pD 2.4) showing the spectral assignments; lower
2D-NOESY NMR spectrum (700 MHz, pD 2.4, 298 K) for [H2L4a 2+
showing
observed correlations.
]
0.14 ppm with a coupling constant of −16 Hz at 298 K. As the
temperature increased, coalescence phenomenon was
a
observed with Tc estimated to be 360 K. An estimate of the acti-
vation energy associated with this dynamic exchange process,
based on a conventional two-site Eyring analysis, gave a free
energy of activation of 74 ( 2) kJ mol−1. This relatively high
energy barrier to interconversion of the major solution confor-
mers can be attributed to the difficulty of exchanging chair or
twisted chair conformers in which the quaternary substituents
exchange sites. This process exchanges the axial/equatorial
positions of the observed, methylene protons (Scheme 8).
Conclusions
These 2D-NOESY and dynamic NMR experiments offer a
simple explanation for the pH-dependent ligand speciation of
the series of ligands, L1–L4, and their behaviour in binding
Ga3+ at pH 2, 3 and 5.2 It was found that the C-Me series of
ligands, L4a/L4b bound 68Ga quickly, but gave rise to more than
Scheme 8
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one type of radiolabelled complex, over the whole pH range, of Synthesis
differing relative stability. In contrast, the C-Ph series of
Details of the synthesis of compounds 9, 11–13, 15, 18–20 and
ligands H3L1 and H3L3 were given in the ESI† of the related
preliminary communication.2
ligands, L1–L3, bind 68Ga rapidly at pH ≥ 3.5 to produce one
major stable solution species, and only at lower pH gave rise to
additional species of inferior kinetic stability. Thus, if the
forward rate of Ga complexation is fast with respect to the rate
of interconversion of the major ligand solution conformers,
‘kinetically trapped’ metal complexes of lower stability will
form, by binding to the isolated EDDA or NDA moieties
1,4-Bis(2,4-dimethoxybenzyl)-6-phenyl-1,4-diazepan-6-ol, 6.
(EDDA:
ethylenediaminediacetate;
NDA-aminodiacetate)
(Scheme 2).
Therefore, the ligands L1–L3, populating a preferred major
solution conformer that reduces the likelihood of formation of
the less stable metal complexes lacking cooperative N3O3 lig-
ation, are excellent candidates for the rapid radiolabelling of
Ga3+ and related small tripositive metal ions that are similar in
size. Crystal structures of the Ga3+ complexes of L1, L3 and
L4a 3,24 have revealed formation of the expected N3O3 binding
polyhedron, in which the seven-membered ring adopts a chair
conformation. Detailed analysis of this structural work has
been reported elsewhere.27
The nitro-compound, 5, (0.05 g, 0.10 mmol) was dissolved in
ethanol (20 mL) and the solution boiled under reflux. The sol-
volysis reaction was monitored using TLC (hexane : ethyl
acetate; 65 : 35). Once the precursor (Rf = 0.55) had been con-
sumed, solvent was removed under reduced pressure and the
resulting oil re-dissolved in chloroform (50 mL) and washed
successively with aqueous potassium carbonate solution (2 ×
50 mL, 0.1 M) and water (50 mL), dried over MgSO4, filtered
and solvent removed under reduced pressure. Purification by
silica gel column chromatography (hexane → 50% ethyl
acetate) yielded a yellow oil (0.017 g, 34%). Rf = 0.45 (hexane :
ethyl acetate; 50 : 50). δH (CDCl3, 700 MHz): 2.53 (2H, m, H4,5);
2.76 (2H, d, J 13, H2,7); 2.80 (2H, m, H4,5); 3.18 (2H, d, J 13,
H2,7); 3.67 (2H, d, J 4, H8); 3.74 (2H, d, J 4, H8); 3.78 (6H, s,
H16); 3.79 (6H, s, H15); 6.41 (2H, d, J 9, H11); 6.44 (2H, s, H13);
7.16 (2H, d, J 9, H10); 7.20 (1H, t , J 8, H4′); 7.30 (2H, t, J 8, H3′);
7.48 (2H, d, J 8, H2′). δC(CDCl3, 176 MHz): 54.0 (C4/5); 55.3
(C16); 55.3 (C15); 56.8 (C8); 67.6 (C2,7); 74.7 (C1′); 98.5 (C13);
103.7 (C11); 120.0 (C9); 124.6 (C2′); 126.4 (C4′); 127.9 (C3′); 131.0
(C10); 146.1 (C1); 158.8 (C12); 160.0 (C14). HRMS ES+ (m/z):
found: 493.2724 [M + H]+; C29H37N2O5 requires 493.2702.
tert-Butyl 1,4-bis(2,4-dimethoxybenzyl)-6-phenyl-1,4-diaze-
pan-6-yl carbamate, 7.
We thank the Association of Commonwealth Universities
for a Scholarship (BPW), and thank Dr Dmitry Yufit (X-ray)
and Dr Juan Aguilar for help with X-ray and NMR analyses.
Experimental
General experimental details for reagents, solvents, chromato-
graphy and spectroscopy have been reported in ref. 2 (ESI†).
Crystallography
The single crystal X-ray data were collected at 120 K on a
Agilent Gemini Ultra (compound 10), a Bruker SMART 1000
(compound 23) and a Bruker SMART 6000 (compound 24)
diffractometers (graphite monochromators, λMoKα,
λ =
0.70073 Å) equipped with Cryostream (Oxford Cryosystems)
open-flow nitrogen cryostats. Each structure was solved by
direct methods and refined by full-matrix least squares on F2
for all data using Olex225 and SHELXTLγ26 software. All non-
hydrogen atoms were refined with anisotropic displacement
parameters, H-atoms in structure 23 and 24 were located on
the difference map and refined isotropically, H atoms in struc-
ture 10 and the methyl group of molecule 24 were placed in
the calculated positions and refined in “riding” mode. The Sodium borohydride (0.013 g, 0.58 mmol) was added portion-
atoms of disordered over two positions tertiary butyl groups in wise to a solution of nickel(II)chloride hexahydrate (0.025 g,
molecule 10 were refined isotropically with fixed SOF = 0.5. 0.11 mmol) in anhydrous methanol (20 mL) cooled in an ice-
Crystallographic data for the structures have been deposited bath, and the mixture stirred for 30 min. The protected amine
with the Cambridge Crystallographic Data Centre as sup- 5 (0.10 g, 0.19 mmol) dissolved in anhydrous methanol (2 mL)
plementary publications CCDC 906040, 911245, 911246 and was added to the reaction mixture, followed by sodium boro-
906039 (compounds 5, 10, 23 and 24 respectively). The struc- hydride (0.028 g, 0.74 mmol) added in portions. The reaction
tures of compounds 24 and 5 have been reported earlier3 and mixture was allowed to warm to room temperature. The reac-
are compared here (CCDC 906039 and CCDC 906040).
tion was monitored by TLC, and once complete the mixture
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was filtered through Celite®, and the insoluble borate salts MgSO4, filtered and solvent removed under reduced pressure
washed with ice-cold methanol. The filtrates were combined, to yield a colourless oil.
and the solvent removed under reduced pressure. The result-
Di-tert-butyl dicarbonate (0.042 g, 0.19 mmol) was added
ing residue was re-dissolved in chloroform (40 mL) and gradually, to a solution of the amine and triethylamine
washed successively with aqueous potassium carbonate solu- (0.029 g, 0.29 mmol) in chloroform (15 mL), and the mixture
tion (2 × 30 mL, 0.1 M) and water (30 mL), dried over MgSO4, stirred at room temperature. The reaction was monitored by
filtered and the solvent removed under reduced pressure. Puri- LS-ES MS, to follow consumption of starting material. Once
fication by silica gel column chromatography (hexane → 20% complete, solvent was removed and the residue re-dissolved in
ethyl acetate) afforded a colourless oil (0.075 g, 78%). Rf = 0.35 chloroform (15 mL) and washed successively with aqueous
(hexane : ethyl acetate; 50 : 50). δH (CDCl3, 500 MHz): 2.16 (3H, sodium hydroxide (2 × 15 mL, 0.5 M) and water (3 × 10 mL),
s, H7); 2.66 (2H, m, H5); 2.74 (2H, m, H4); 3.46 (2H, s, H8); 3.67 dried over MgSO4, filtered and the solvent removed under
(2H, s, H17); 3.75 (6H, s, H15/16,24/25); 3.79 (6H, s + s, H15/16,24/25); reduced pressure to yield a colourless oil. Purification by silica
3.86 (2H, s, H2); 6.41 (4H, m, H13,14,22,23); 7.08 (1H, d, J 8, H20); gel column chromatography (hexane → 60% ethylacetate)
7.18 (1H, d, J 8, H11); 7.33 (3H, m, H3′,4′); 7.59 (2H, m, H2′). δC afforded a colourless oil (0.005 g, 9%). Rf = 0.35 (hexane :
(CDCl3, 125 MHz): 42.52 (C7); 51.24 (C4); 53.23 (C17); 53.43 ethylacetate, 50 : 50). δH (CDCl3, 700 MHz): 1.36 (3H, s, H19);
(C2); 54.34 (C5); 55.40 (C15/16,24/25); 55.50 (C15/16,24/25); 55.77 2.48 (4H, s, H8); 2.72 (2H, m, H4,5); 3.35 (2H, m, H4,5); 3.46
(C8); 98.64 (C13/14/22/23); 98.71 (C13/14/22/23); 104.09 (C13/14/22/23); (2H, d, J 13, H2,7); 3.59 (2H, d, J 13, H2,7); 3.73 (6H, s, H15/16);
104.28 (C13/14/22/23); 117.15 (C18); 119.16 (C9); 126.31 (C2′); 3.78 (6H, s, H15/16); 6.37 (2H, d, J 8, H11); 6.41 (2H, s, H13); 7.14
128.52 (C3′/4′); 128.99 (C3′/4′); 131.82 (C11); 132.46 (C20); 136.52 (4H, m, H3′,4′,10); 7.35 (4H, m, H2′). δC (CDCl3, 176 MHz): 28.25
(C1′); 154.26 (C1); 159.03 (C10); 159.34 (C19); 160.24 (C12/21); (C19); 55.33 (C15/16); 55.53 (C15/16); 57.19 (C8); 57.33 (C2/7); 57.84
161.01 (C12/21). HRMS ES+ (m/z): found 508.2818 [M + H]+; (C1); 68.77 (C4/5); 78.61 (C18); 98.65 (C11); 103.73 (C13); 120.21
C29H38N3O5 requires 508.2811.
(C9); 125.17 (C2′); 125.75 (C3′); 125.92 (C4′); 131.12 (C14); 146.19
(E)-2-((2,4-Dimethoxybenzyl)(2-((2,4-dimethoxybenzyl)(methyl)- (C17); 159.46 (C12); 159.76 (C10). HRMS ES+ (m/z): found
amino)ethyl)amino)-1-phenylethanone oxime, 8.
592.3406 [M + H]+; C34H46N3O6 requires 592.3387; found
614.3221 [M + Na]+; C34H45N3NaO6 requires 614.3206.
6-Phenyl-1,4-diazepan-6-amine, 3c.
Trifluoroacetic acid (1 mL) was added to a solution of the pro-
tected triamine 8 (0.010 g, 0.017 mmol) in dichloromethane
(1 mL), and the mixture stirred at room temperature. The reac-
tion was monitored using LC-ESI MS, and once complete, the
solvent was removed by lyophilisation. Excess trifluoroacetic
acid was removed through repeated addition and removal of
dichloromethane (3 × 2 mL) and subsequently methanol (3 ×
2 mL), to afford a white solid (0.004 g). δH (CD3OD, 600 MHz):
3.37 (2H, m, H4,5); 3.42 (2H, d, J 15, H2,7); 3.56 (2H, m, H4,5);
3.70 (2H, d, J 15, H2,7); 7.29 (1H, t, H4′); 7.35 (2H, t, H2′); 7.38
(2H, d, H2′). δC (CD3OD, 151 MHz): 43.77 (C4,5); 53.13 (C2,7);
65.88 (C1); 124.76 (C2′); 125.00 (C4′); 129.48 (C3′). HRMS ES+
(m/z): found 192.1485 [M + H]+; C11H18N3 requires 192.1501.
The synthesis of the NHBoc-protected primary amine, 8, was
carried out in two steps, involving reduction of the nitro-func-
tionality, followed by Boc-protection.
An aqueous slurry of RANEY® nickel (0.010 g) was washed
with methanol (3 × 25 mL) and ethanol added (10 mL). The
suspension was then transferred into a solution of 5 (0.050 g,
0.096 mmol) in ethanol (25 mL). The flask was evacuated and
back-filled with hydrogen gas using four vacuum-purge cycles,
and the mixture stirred at 298 K under an atmosphere of
hydrogen. The reaction was monitored by TLC for formation of
the primary amine. Once complete (∼3 h), the solution was
decanted, and the solid washed with methanol (3 × 20 mL).
The washings and decanted solution were combined, removed
under reduced pressure and re-dissolved in methanol (25 mL).
Remaining RANEY® nickel and insoluble by-products where
removed by filtration through a base washed Celite® filter, and
the solvent was then removed under reduced pressure. The
resulting oil was re-dissolved in chloroform : isopropanol
(80 : 20; 20 mL) and washed successively with aqueous sodium
hydroxide (2 × 20 mL, 0.5 M) and water (15 mL), dried over
tert-Butyl
2,2′-(6-nitro-6-phenyl-1,4-diazepane-1,4-diyl)di-
acetate, 10.
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tert-Butyl bromoacetate (0.10 g, 0.52 mmol) was added drop-
tert-Butyl 2,2′-(6-(2-tert-butoxy-2-oxoethylamino)-6-phenyl-
wise to a mixture of potassium carbonate (0.072 g, 0.52 mmol) 1,4-diazepane-1,4-diyl)diacetate, 14.
and 9 (0.029 g, 0.13 mmol) in acetonitrile (10 mL). The reac-
tion mixture was stirred at 35 °C for 24 h, and solvent removed
under reduced pressure. The resulting oil was re-dissolved in
chloroform (20 mL) and washed successively with aqueous pot-
assium carbonate solution (2 × 20 mL, 0.1 M) and water
(20 mL), dried over MgSO4, filtered and solvent removed under
reduced pressure. Purification by silica gel column chromato-
graphy (hexane : ethyl acetate, 95 : 5) yielded a white solid
(0.036 g, 62%). Rf = 0.49 (hexane : ethyl acetate; 65 : 35).
m.p. 78–90 °C. δH (CDCl3, 700 MHz): 1.44 (18H, s, H11); 2.93
tert-Butyl-bromoacetate (0.29 g, 1.6 mmol) was added to a sol-
(2H, m, H4,5); 3.03 (2H, m, H4,5); 3.38 (2H, d, J 17, H8); 3.56
(2H, d, J 17, H8); 3.63 (2H, d, J 15, H2,7); 3.96 (4H, d, J 15, H2,7);
7.24 (2H, d, J 8, H2′); 7.31 (2H, m, H3′,4′). δC (CDCl3, 176 MHz):
28.20 (C11); 55.93 (C4,5); 60.33 (C8); 62.87 (C2,7); 81.15 (C10);
97.99 (C1′); 124.62 (C2′); 128.52 (C4′); 128.81 (C3′); 138.68 (C1);
170.90 (C9). HRMS ES+ (m/z): found: 450.2612 [M + H]+;
C23H36N3O6 requires 450.2604. The structure of 7 was con-
ution of 12 (0.050 g, 0.3 mmol) and potassium carbonate
(0.31 g, 2.1 mmol) in acetonitrile (30 mL), and the mixture
stirred for 18 h at 40 °C under argon. The solvent was removed
under reduced pressure and the resulting oil re-dissolved in
chloroform (20 mL) and washed successively with aqueous pot-
assium carbonate solution (2 × 20 mL, 0.1 M) and water
(20 mL), dried over magnesium sulphate, filtered and solvent
removed under reduced pressure. Purification by silica gel
column chromatography (hexane → 5% ethyl acetate) yielded a
yellow oil (0.051 g, 32%). Rf = 0.60 (hexane : ethyl acetate;
65 : 35). δH (CDCl3, 700 MHz): 1.37 (18H, s, H11); 1.38 (9H, s,
H15); 1.89 (1H, br. s, NH); 2.83 (2H, d, J 15, H4,5); 2.87 (4H, s,
H2,7); 3.04 (2H, s, H12); 3.27 (2H, d, J 15, H4,5); 3.33 (4H, s, H8);
7.14 (1H, t, J 7, H4′); 7.24 (2H, t, J 7, H3′); 7.45 (2H, d, J 7, H2′).
δC (CDCl3, 176 MHz): 28.10 (C11); 28.21 (C15); 45.57 (C12); 56.44
(C2,7); 61.62 (C8); 62.08 (C1′); 65.54 (C4,5); 80.88 (C10,14); 126.51
(C2′); 126.67 (C4′); 128.26 (C3′); 144.48 (C1); 171.01 (C9); 171.75
(C13). HRMS ES+ (m/z): found: 534.3556 [M + H]+; C29H48N3O6
requires 534.3543.
firmed by single crystal X-ray diffraction: C23H35N3O6, Mr
=
449.54, monoclinic (P21/c); a = 21.3378(19) Å, b = 11.5579(10) Å,
c = 10.3203(9) Å, V = 2503.9(4) Å3, β = 100.329(9)°, Z = 4; μ =
0.086 mm−1, Dcalc. = 1.192 mg mm−3, T 120(2) K; 5463 inde-
pendent reflections (Rint = 0.1564), R1 = 0.0899, ωR2 = 0.1741
(I > 2σ(I)). CCDC 911245.
Diethyl
2,2′-(6-nitro-6-phenyl-1,4-diazepane-1,4-diyl)di-
acetate, 11.
tert-Butyl 2,2′-(1,4-bis(2-tert-butoxy-2-oxoethyl)-6-phenyl-1,4-
diazepan-6-ylazanediyl)diacetate, 16.
Ethyl bromoacetate (0.061 g, 0.52 mmol) was added dropwise
to stirred solution of potassium carbonate (0.072 g,
a
0.52 mmol) and 9 (0.029 g, 0.13 mmol) in acetonitrile (10 mL).
The reaction mixture was stirred at 35 °C for 24 h, and solvent
removed under reduced pressure. The resulting oil was re-dis-
solved in chloroform (20 mL) and washed successively with
aqueous potassium carbonate solution (2 × 20 mL, 0.1 M) and
water (20 mL), dried over MgSO4, filtered and solvent removed tert-Butyl-bromoacetate (0.14 g, 0.72 mmol) was added to a
under reduced pressure. Purification by silica gel column solution of 12 (0.050 g, 0.12 mmol) and potassium carbonate
chromatography (hexane → 20% ethyl acetate) yielded a yellow (0.13 g, 0.96 mmol) in acetonitrile (20 mL), and the mixture
oil (0.034 g, 66%). Rf = 0.27 (hexane : ethyl acetate, 65 : 35). δH stirred for 18 h at 50 °C under argon. The solvent was removed
(CDCl3, 700 MHz): 1.26 (6H, t, J 7, H11); 2.96 (2H, m, H4,5); 3.04 under reduced pressure and the resulting oil re-dissolved in
(2H, m, H4,5); 3.49 (2H, d, J 18, H8); 3.64 (2H, d, J 15, H2,7); chloroform (20 mL) and washed successively with aqueous pot-
3.67 (2H, d, J 18, H8); 3.97 (2H, d, J 15, H2,7); 7.24 (2H, d, J 8, assium carbonate solution (2 × 20 mL, 0.1 M) and water (2 ×
H2′); 7.32 (2H, m, H3′,4′). δC (CDCl3, 176 MHz): 14.26 (C11); 20 mL), dried over MgSO4, filtered and solvent removed under
55.85 (C4,5); 59.41 (C8); 60.40 (C10); 62.70 (C2,7); 97.76 (C1′); reduced pressure. Purification by silica gel column chromato-
124.63 (C2′); 128.62 (C4′); 128.84 (C3′); 138.41 (C1); 171.53 (C9). graphy (hexane → 5% ethyl acetate) afforded the title com-
HRMS ES+ (m/z): found: 394.1968 [M + H]+; C19H28N3O6 pound as a yellow oil (0.009 g, 12%). Rf = 0.75 (hexane : ethyl
requires 394.1978.
acetate; 65 : 35). δH (CDCl3, 700 MHz): 1.42 (18H, s, H11/15);
This journal is © The Royal Society of Chemistry 2013
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1.43 (18H, s, H11/15); 2.72 (2H, m, H4,5); 2.84 (2H, m, H4,5); 3.11 under reduced pressure, the residue re-dissolved in
(2H, d, J 15, H2,7); 3.29 (4H, d + d, H2,7+8); 3.36 (2H, d, J 17, dichloromethane : methanol (1 : 1; 2 mL) and evaporated. This
H8); 3.59 (4H, s, H12); 7.17 (1H, t, J 8, H4′); 7.27 (2H, t, J 8, H3′); procedure was repeated twice, and with methanol. The result-
7.73 (2H, d, J 8, H2′). δC (CDCl3, 176 MHz): 28.08 (C11/15); 28.19 ing solid was dissolved in water (10 mL) and washed with
(C11/15); 53.66 (C12); 59.12 (C4,5); 62.04 (C8); 65.41 (C2,7); 67.37 dichloromethane (10 mL). Removal of solvent under reduced
(C1); 80.06 (C10/14); 80.84 (C10/14); 126.46 (C4′); 127.08 (C2′); pressure and drying in vacuo afforded a white solid (0.039 g,
128.05 (C3′); 147.73 (C1′); 170.54 (C9); 172.13 (C13). HRMS ES+ 71%). δH (D2O, pD = 2.6, 600 MHz): 2.62 (3H, s, H12); 3.15 (2H,
(m/z): found 648.4227 [M + H]+; C35H58N3O8 requires 648.4224; m, H4,5); 3.44 (2H, m, H4,5); 3.44 (2H, d, J 14, H2,7); 3.67 (3H,
found 670.4058 [M + Na]+; C35H57N3NaO8 requires 670.4043.
m, H4/5,10); 3.83 (3H, m, H4/5,8); 3.88 (2H, d, J 14, H2,7); 7.30
tert-Butyl 2,2′-(6-((2-tert-butoxy-2-oxoethyl)(methyl)amino)- (1H, m, H4′); 7.35 (2H, m, H3′); 7.40 (2H, m, H2′). δC (D2O, pD =
6-phenyl-1,4-diazepane-1,4-diyl)diacetate, 17.
2.6, 151 MHz): 32.60 (C12); 51.89 (C4/5); 53.19 (C4/5); 58.73
(C10); 59.00 (C8); 63.00 (C2,7); 71.85 (C1); 128.87 (C4′); 129.05
(C3′); 129.44 (C2′); 170.04 (C9); 172.80 (C11). HRMS ES+ (m/z):
found 380.1818 [M + H]+; C18H26N3O6 requires: 380.1822.
Found: C, 43.2; H, 4.33; N, 6.84%. [C18H25N3O6]·2CF3COOH
requires: C, 43.5; H, 4.48; N, 6.92%.
6-Phenyl-1,4-diazepan-6-ol, 21.
Methyl iodide (0.032 g, 0.023 mmol) was added to a solution
of 14 (0.03 g, 0.056 mmol) and potassium carbonate (0.032 g,
0.023 mmol) in acetonitrile (30 mL), and the mixture stirred
for 24 hours at 30 °C, under argon. The solvent was removed
under reduced pressure and the resulting oil re-dissolved in
chloroform (20 mL) and washed successively with aqueous pot-
assium carbonate solution (2 × 20 mL, 0.1 M) and water
(20 mL), dried over potassium carbonate, filtered and solvent
removed under reduced pressure. Purification by silica gel
column chromatography (hexane → 5% ethyl acetate) yielded a
yellow oil (0.01 g, 45%). Rf = 0.60 (SiO2, hexane : ethyl acetate;
65 : 35). δH (CDCl3, 700 MHz): 1.38 (18H, s, H11); 1.39 (9H, s,
H15); 2.23 (3H, s, H16); 2.70 (2H, m, H4,5); 2.80 (4H, m, H4,5);
3.06 (2H, d, J 15, H2,7); 3.13 (2H, d, J 15, H2,7); 3.26 (2H, d, J 17,
H8); 3.30 (2H, d, J 17, H8); 3.47 (2H, s, H12); 7.11 (1H, t, J 8,
H4′); 7.21 (2H, t, J 8, H3′); 7.63 (2H, d, J 8, H2′). δC (CDCl3,
176 MHz): 28.12 (C11); 28.20 (C15); 45.57 (C12); 38.40 (C16);
54.73 (C12); 58.84 (C4,5); 62.19 (C8); 64.11 (C2,7); 66.55 (C1′);
80.10 (C14); 80.84 (C10); 126.27 (C4′); 126.94 (C2′); 127.96 (C3′);
148.05 (C1); 170.63 (C9); 172.37 (C13). HRMS ES+ (m/z): found:
548.3704 [M + H]+; C30H50N3O6 requires 548.370.
3,6-Bis(2,4-dimethoxybenzyl)-1-phenyl-3,6-diazepan-1-ol (0.100 g,
0.52 mmol) was dissolved in trifluoroacetic acid–dichloro-
methane (1 : 1, 2 mL) and left to stir for 2 days at room tempera-
ture. The solvent was removed under reduced pressure, the
residue re-dissolved in dichloromethane and evaporated. This
procedure was repeated twice. The residue was recrystallised
from methanol–dichloromethane (1 : 1) to afford a white solid
(0.029 g, 76%). δH (CD3OD, 700 MHz): 2.83 (2H, d, J 14, H2,7);
2.92 (2H, m, H4,5); 3.07 (2H, m, H4,5); 3.19 (2H, d, J 14, H2,7);
7.20 (1H, t, J 8, H4′); 7.37 (2H, t, J 8, H3′); 7.45 (2H, d, J 8, H2′).
δC (CD3OD, 176 MHz): 48.6 (C4,5); 58.9 (C2,7); 76.2 (C1); 124.3
(C2′); 126.6 (C4′); 127.8 (C3′); 145.4 (C1′). HRMS ES+ (m/z):
found: 193.1271 [M + H]+; calculated for C11H17N2O: 193.1341.
tert-Butyl 2,2′-(6-(2-tert-butoxy-2-oxoethoxy)-6-phenyl-1,4-di-
azepane-1,4-diyl)diacetate, 22.
2,2′-(6-((Carboxymethyl)(methyl)amino)-6-phenyl-1,4-diaze-
pane-1,4-diyl)diacetic acid, H3L2.
tert-Butyl-bromoacetate (0.10 g, 0.52 mmol) was added to a solu-
tion of 21 (0.02 g, 0.10 mmol) and caesium carbonate (0.10 g,
0.52 mmol) in acetonitrile (15 mL), and the mixture stirred for
18 h at 363 K under argon. The solvent was removed under
reduced pressure and the resulting oil re-dissolved in chloro-
form (15 mL) and washed successively with aqueous potass-
The triester 14 (0.050 g, 0.091 mmol) was dissolved in ium carbonate solution (2 × 15 mL, 0.1 M) and water (10 mL),
trifluoroacetic acid–dichloromethane (1 : 1; 2 mL) and left to dried over MgSO4, filtered and solvent removed under reduced
stir for 2 d at room temperature. The solvent was removed pressure. Purification by silica gel column chromatography
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(hexane → 20% ethyl acetate) afforded a colourless oil (0.018 g,
2,2′-(6-(Carboxymethoxy)-6-phenyl-1,4-diazepane-1,4-diyl)-
33%). Rf = 0.25 (hexane : ethyl acetate; 50 : 50). δH (CDCl3, diacetic acid, H3L6.
700 MHz): 1.42 (18H, s, H11/15); 1.43 (9H, s, H11/15); 1.46 (9H, s,
H19); 1.48 (9H, s, H16); 2.50 (1H, d, J 7, H8/12); 2.59 (1H, d, J 14,
H2/7); 2.66 (1H, d, J 7, H8/12); 2.74 (1H, d, J 14, H2/7); 2.89 (1H,
m, H4/5); 2.93 (1H, m, H4/5); 3.01 (2H, m, H4,5); 3.09 (1H, d,
J 14, H2/7); 3.36 (3H, m, H2/7,8,12); 7.22 (1H, t, J 8, H4′); 7.31 (2H,
t, J 8, H3′); 7.50 (1H, d, J 8, H2′). δC (CDCl3, 176 MHz): 28.08
(C11/15/19); 28.14 (C11/15/19); 28.20 (C11/15/19); 37.23 (C16); 55.18
(C4/5); 55.47 (C4/5); 60.70 (C8); 63.64 (C12); 64.19 (C2/7); 66.37
(C2/7); 73.30 (C1); 80.78 (C10/14/18); 81.10 (C10/14/18); 81.46 (C10/
14/18); 82.90 (C17); 124.56 (C2′); 126.67 (C4′); 128.03 (C3′); 145.23
The triester 22 (0.020 g, 0.037 mmol) was dissolved in TFA :
(C1′); 170.84 (C9/13); 170.91 (C9/13). HRMS ES+ (m/z): found:
535.3362 [M + H]+; C29H47N2O7 requires 535.3383; found:
557.3192 [M + Na]+; C29H46N2NaO7 requires 557.3203.
tert-Butyl 2,2′-(6-hydroxy-6-phenyl-1,4-diazepane-1,4-diyl)di-
acetate, 23.
dichloromethane (1 : 1, 2 mL) and left to stir for 2 days at room
temperature. The solvent was removed under reduced
pressure, the residue re-dissolved in dichloromethane :
methanol (1 : 1; 2 mL) and evaporated. This procedure was
repeated twice, and with methanol. The resulting solid was
then dissolved in water (10 mL) and washed with dichloro-
methane (10 mL). Removal of the solvent under reduced
pressure afforded, after drying in vacuo, a white solid (0.014 g,
81%). δH (D2O, pD = 2.7, 700 MHz): 2.70 (1H, m, H4/5); 2.79
(1H, m, H4/5); 2.98 (1H, m, H2/7); 3.25 (3H, m, H2,7,12); 3.36
(2H, m, H2/7, 4/5); 3.52 (1H, m, H4/5); 3.81 (4H, m, H8,10); 4.01
(1H, d, H12); 7.30–7.33 (5H, m, Ph H). δC (D2O, pD = 2.7,
176 MHz): 34.18 (C4/5); 49.87 (C2/7); 55.69 (C4/5); 59.38 (C8/10);
62.75 (C12); 63.38 (C2/7); 72.90 (C1); 124.42 & 128.46 & 128.91
(C2′,3′,4′) 141.27 (C1′); 169.51 & 169.55 (C9/11); 175.20 (C13).
HRMS ES+ (m/z): found 389.1337 [M + Na]+; C17H22N2NaO7
requires 389.1325. Found: C, 47.8; H, 4.97; N, 5.71%.
[C17H22N2O7]·CF3COOH requires: C, 47.5; H, 4.83; N, 5.83%.
2,2′-(6-Hydroxy-6-phenyl-1,4-diazepane-1,4-diyl)diacetic acid,
H2L7.
tert-Butyl-bromoacetate (0.20 g, 1.0 mmol) was added dropwise
to a mixture of potassium carbonate (0.14 g, 1.0 mmol) and 21
(0.05 g, 0.26 mmol) in acetonitrile (15 mL), and the mixture
stirred at 35 °C for 18 h under argon. The solvent was removed
under reduced pressure and the resulting oil re-dissolved in
chloroform (25 mL) and washed successively with aqueous pot-
assium carbonate solution (2 × 25 mL, 0.1 M) and water
(25 mL), dried over MgSO4, filtered and solvent removed under
reduced pressure. Purification by silica gel column chromato-
graphy (hexane → 20% ethyl acetate) yielded white solid
(0.084 g, 74%). Rf = 0.15 (hexane : ethyl acetate, 65 : 35).
m.p. 88–97 °C. Single crystals of 23 were grown by slow evapor-
ation of saturated ethanol : dichloromethane solution. δH The diester 23 (0.050 g, 0.12 mmol) was dissolved in trifluoro-
(CDCl3, 700 MHz): 1.43 (18H, s, H11); 2.64 (2H, d, J 14, H2,7); acetic acid–dichloromethane (1 : 1, 2 mL) and left to stir for 2
2.94 (2H, m, H4,5); 3.01 (2H, m, H4,5); 3.38 (2H, d, J 14, H2,7); days at room temperature. The solvent was removed under
3.40 (2H, s, H8); 5.02 (1H, br. s, H12); 7.22 (1H, t, J 8, H4′); 7.31 reduced pressure, the residue re-dissolved in dichloromethane
(2H, t, J 8, H3′); 7.50 (2H, d, J 8, H2′). δC (CDCl3, 176 MHz): and evaporated. This procedure was repeated twice, and also
28.15 (C11); 54.77 (C4,5); 60.67 (C8); 66.66 (C2,7); 73.78 (C1′) with methanol. The resulting solid was dissolved in water
81.12 (C10); 124.57 (C2′); 126.70 (C4′); 128.05 (C3′); 145.07 (C1); (15 mL) and washed with dichloromethane (15 mL). Removal
170.87 (C9). HRMS ES+ (m/z): found: 421.2714 [M + H]+; of solvent under reduced pressure afforded a white solid
C23H37N2O5 requires 421.2702. The structure of 20 was con- (0.026 g, 51%). δH (D2O, pD 3.58, 700 MHz): 3.44 (2H, d, J 14,
firmed by single crystal X-ray diffraction: C23H36N2O5, Mr
=
H2,7); 3.72 (2H, m, H4,5); 3.84 (2H, m, H4,5); 3.89 (4H, s, H8);
420.54, triclinic (P1); a = 5.7906(7) Å, b = 9.5843(11) Å, c = 3.89 (2H, d, J 14, H2,7); 7.33 (1H, m, H4′); 7.34 (2H, br. s, H2′,3′).
20.978(2) Å, V = 1145.6(2) Å3, α = 81.025(10)°, β = 87.158(10)°, δC (D2O, pD 3.6, 176 MHz): 51.78 (C4,5); 58.75 (C8); 62.88 (C2,7);
ˉ
γ = 85.460(10)°, Z = 2; μ = 0.085 mm−1, Dcalc. = 1.219 mg mm−3
,
71.75 (C1′); 124.09 (C2′); 128.92 (C4′); 129.08 (C3′); 140.57 (C1);
T 120(2) K; 5749 independent reflections (Rint = 0.0595), R1 = 169.54 (C9). HRMS ES+ (m/z): found: 309.1450 [M + H]+;
0.0563, ωR2 = 0.1154 (I > 2σ(I)). CCDC 911246.
C15H21N2O5 requires 309.1450. Found: C, 48.0; H, 4.84; N,
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6.69). [C15H20N2O5]·CF3COOH requires: C, 48.3; H, 5.01; N,
6.63%.
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2838 | Org. Biomol. Chem., 2013, 11, 2827–2838
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