Reaction chemistry of tri-substituted mesitylene derivatives and the synthesis of sterically buttressed 1,3,5-triaminocyclohexyl ligands

Article abstract of DOI:10.1039/a701364g

The sterically buttressed triamine cis,cis-2,4,6-trimethyl-1,3,5-triaminocyclohexane is weakly basic in aqueous solution (pK_a: 7.83, 6.73, 5.15; 298 K) because of steric inhibition to solvation. As a result of intramolecular hydrogen-bonding an

Full text of DOI:10.1039/a701364g

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Reaction chemistry of tri-substituted mesitylene derivatives and the
synthesis of sterically buttressed 1,3,5-triaminocyclohexyl ligands
David Parker,* Kanthi Senanayake, Jouko Vepsailainen, Stefania Williams,
Andrei S. Batsanov and Judith A. K. Howard
Department of Chemistry, University of Durham, South Road, Durham, UK DH1 3LE
The sterically buttressed triamine cis,cis-2,4,6-trimethyl-1,3,5-triaminocyclohexane is weakly basic in
aqueous solution (pKa: 7.83, 6.73, 5.15; 298 K ) because of steric inhibition to solvation. As a result of
intramolecular hydrogen-bonding and stabilising σC᎐H –σ*C᎐N interactions, the free amine and its
monoprotonated salt adopt a conformation in which the three amino groups are axially disposed.
It possesses a reduced reactivity in SN 2 reactions and may be converted via selective alkylation or
condensation to polydentate ligands incorporating carboxylate, hydroxyphenyl or phosphinate groups.
An intramolecular hydride transfer mechanism accounts for the formation of a stable bicyclic amidine
formed during acidic hydrolysis of a tricyclic bis-aminal derived from the parent triamine by a
phosphinoxymethylation. The crystal structures of two of the mesitylene derivatives have been
determined.
Ligands that are based on a cis,cis-1,3,5-trioxy- or -triamino-
cyclohexyl moiety have been studied as facially coordinating
molecules for the complexation of relatively small metal ions.1–4
Complexing agents which engender 6-ring chelate-rings on
metal binding prefer to bind to metals with low coordination
numbers (e.g. 4, 5 and 6) in complexes that possess relatively
short M᎐X bond lengths and relatively large X᎐M᎐X bond
angles.5 Thus the hexacoordinating trioxytriamide 1a binds
exerts other effects: the steric buttressing of the alkyl groups for
example may tend to inhibit ligand solvation. Although there is
relatively little difference in the effective steric demand of a
single methyl group compared to an amino group in polar
media (A-values are 7.3 for Me and 7.1 for NH2 in aqueous
methoxyethanol),8 the axial amino groups may be expected to
undergo intramolecular H-bonding to alleviate lone-pair repul-
sion. These two effects should lead to the compound 2a prefer-
ring the conformer with the amino groups axial. While ligands
based on 2a may not possess the same degree of conforma-
tional bias that is present in related cis-substituted cyclohexyl
moieties, such as Kemp’s tri-acid and its derivatives,9 they may
serve as useful platforms upon which to explore the coordin-
ation behaviour of sterically-buttressed ligands derived there-
from and the role of neighbouring group effects operating in
such stereoelectronically well-defined systems.
Y
X
O
O
NH2
NH2
NH2
R
R
O
R
X
1a X = Y = CONBu2
b X = CONBu2, Y = n-Pr
2a R = Me
b R = H
c R = OH
A suitable precursor for the synthesis of such cis-substituted
cyclohexyl ligands is trinitromesitylene10 3. Reduction of the
nitro groups affords the triamine 4 which may be reduced under
sodium preferentially with respect to the larger potassium ion
(Na/K selectivity is 103.1)1 while the pentacoordinate analogue
1b binds the small Liϩ ion preferentially over Naϩ (Li/Na select-
ivity is 102.25). With ligands based on cis,cis-1,3,5-triamino-
cyclohexane, previous work has focused on complexes of the
parent system 2b and of tri-N-substituted ligands derived there-
from.3,4a More recently some attention has been paid to the
coordination chemistry of ligands derived from 1,3,5-triamino-
1,3,5-trideoxy-cis-inositol, 2c.4b,6 We were attracted by the
related ligand 2a, as a ligating sub-unit for study of its coordin-
ation properties. In this system, the three methyl groups may
adopt equatorial positions in one limiting chair conformation
and in the other limiting chair structure the amino-groups are
placed equatorial (Scheme 1). In the triprotonated amine, this
X
X
Me
Y
Me
Me
Me
X
Y
X
Me
Me
3
X = NO2
X = NH2
6
X = NO2, Y = NH2
4
7a X = NO2, Y = NCHPh
b X = NO2, Y = NHCH2Ph
c X = NH2, Y = NHCH2Ph
5a X = NCHPh
b X = NHCH2Ph
stereocontrolled hydrogenation catalysis to the desired cis,cis-
triamine 2a. The sterically hindered aromatic triamine 4 and
congeners such as 6 are themselves potentially interesting pre-
cursors in the synthesis of dendrimer architectures: the but-
tressing methyl groups force the N-substituted amine lone-pairs
out of conjugation enhancing nucleophilicity but inhibiting
poly-N-substitution.
We report the synthesis of 2a and of dibasic N3O2 and tri-
basic N3O3 ligands, including carboxy, phenoxy and phosphin-
oxy derivatives in addition to some simple reaction chemistry
based on the aromatic nitro and amino-derivatives. Aspects of
this work have appeared in a preliminary communication.7
Scheme 1
conformer is preferred in order to minimise coulombic repul-
sion, and the X-ray structure of the trication [H32a]3ϩ confirms
this preference.7 The presence of the methyl groups in ligand 2a
J. Chem. Soc., Perkin Trans. 2, 1997
1445

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NMR spectral details. In cyclohexyl systems, the stereo-
electronic preference for a C᎐X (X = Hal, OR, NR2) bond to be
antiperiplanar to a C᎐H bond arises from a favourable σC᎐H
–
σ*C᎐X interaction.11 When the CHMe proton is anti to the elec-
tronegative group, this stereoelectronic effect manifests itself in
a reduction of the vicinal coupling constant J(Ha,He) (Scheme
2) by 1 or 2 Hz, with respect to that seen in the alternative
Scheme 2
Fig. 1 Molecular structure of 5a in the crystal, showing positions A
(solid) and B (dashed) of the disordered N᎐CHPh group. C᎐N bonds
᎐
᎐
conformer where the CHMe proton is syn to the group X. For
example, when X = OCD3 and R = H, the relevant coupling
constants are 2.5 and 4.1 Hz for the favoured and disfavoured
conformers respectively.12 In CDCl3 (293 K), the observed
coupling constant J (Ha, He) was measured as 3.0 Hz (±0.2)
in both 2a and the N-benzyl derivative 9b. A preliminary
X-ray structural analysis of 9b had previously shown that the
are not conjugated with the central benzene ring, torsion angles around
the C(1)᎐N(1), C(3)᎐N(3), C(1)᎐N(5A), C(1)᎐N(5B) bonds being 76,
74, 61 and 65Њ, respectively.
X
Ar
X
Ar
Ar
Ar
X
Ar
Ar
NH
HN
NH
HN
N
HN
Me
HN
N
R
Me
N
Fig. 2 Molecular structure of 7c in the crystal. The bond geometry at
N(1) and N(3) atoms is pyramidal, at N(5) nearly planar [sums of bond
angles 332(3), 334(3) and 358(5)Њ, respectively]; the latter plane is
inclined by 6(2)Њ to the central benzene ring. The lone pairs at N(1) and
N(3) form angles of 49 and 51Њ with the pπ orbitals of C(1) and C(2).
Bond distances C(1)᎐N(1) 1.439(3), C(3)᎐N(3) 1.437(3), C(5)᎐N(5)
1.406(3) Å.
Me
R
Me
Me
HO
R
Me
8
X = CO2Et, R = Me
11
10
Ar =
9a X = CO2H, R = Me
b X = Ph, R = Me
NO2
c X = CO2H, R = H
Synthesis and characterisation
NHCH2Ph groups were axially disposed.7 The chemical shift
of the CHNH resonance in 2a was independent of solvent,
appearing at 2.8 (±0.05) ppm in CD3OD, CDCl3 and CD2Cl2,
with the same 3 Hz coupling constant. Addition of excess
CF3CO2H to a solution containing 2a in CD3OD, shifted the
Reduction of trinitromesitylene 3 with sodium borohydride in
the presence of copper() acetate in aqueous ethanol afforded
the triamine 4 in a yield of 80%. Condensation of 4 directly
with benzaldehyde under reduced pressure gave the yellow tri-
imine 5a and an X-ray crystallographic analysis of this mole-
cule revealed that the imine double bonds were almost ortho-
gonal to the plane of the aromatic ring (Fig. 1). Hydrogenation
of 5a did not proceed at ambient temperature or pressure using
Pd on C catalysts but over Pt/C in ethanol at 3 atmospheres and
20 ЊC, reduction proceeded cleanly allowing the isolation of the
tri-N-benzylamine 5b. The reduction of 3 could also be carried
out with this Pt/C catalyst giving 4 in 99% yield after a reaction
time of 3 days. When 3 was allowed to react under these condi-
tions for only 1 hour, the partially reduced diamine 6 was
obtained in 47% yield following crystallisation from ethanol.
Condensation of 6 with neat benzaldehyde gave the imine 7a
and subsequent borohydride reduction yielded the diamine 7b.
A crystallographic analysis of the derived amine 7c revealed
that only the N-substituted amine lone-pairs were substantially
out of conjugation with the aryl π molecular orbitals (Fig. 2).
Catalytic hydrogenation of the aromatic ring in 4 required
the use of a rhodium on carbon catalyst, doped with Pd (1% Pd
on Rh/C). Similar catalysts have been used for the stereoselec-
tive reduction of polysubstituted aryl rings, as in the prepar-
ation of 2c.4b Using moderately dilute aqueous sulfuric acid (0.3
mol dmϪ3), hydrogenation of 4 occurred cleanly (20 ЊC, 3 atm
H2, 6 days) to give a 4:1 mixture of the cis,cis- and cis,trans-
diastereoisomers. The desired cis,cis-isomer was separated by
crystallisation of the sulfate salt from H2O–EtOH–CH2Cl2. The
crystallographic analysis of this salt has been reported previ-
ϩ
CHNH3 resonance to higher frequency (3.73 ppm) and the
coupling constant increased to 5.1(3) Hz. In the triprotonated
amine, HaЈ (Scheme 2) is now anti to a methyl group, and the
vicinal coupling constant increases as the stabilising σC᎐H–σ*C᎐X
interaction is lost. When the amino groups are in axial positions
an array of three intramolecular hydrogen bonds is set up with
each group accepting and donating one proton, with the methyl
groups shielding this arrangement from solvent interactions.
Protonation disrupts this ideal arrangement. It therefore seems
likely that in both 2a and 9b, the preferred solution conformer
at room temperature (CDCl3) is the one with the amino groups
placed axial in accord with stabilisation involving intra-
molecular H-bonding and favourable σC᎐H–σ*C᎐X interactions
and with their slightly smaller size with respect to the methyl
groups. Of course, in reality the observed coupling constant is a
weighted average of the J values associated with the two major
chair conformers [eqn. (1)], where ne and na represent the mole
Jobs = neJ(HaЈHeЈ) ϩ naJ(HaHe)
(1)
fractions of each solution conformer and J(HaЈHeЈ) and
J(HaHe) are the geminal coupling constants for the conformers
with the NHR groups equatorial and axial respectively. Vari-
1
able temperature H NMR studies (Ϫ90 to ϩ30 ЊC) of 2a in
CD2Cl2 and CD3OD revealed no significant shifts in either the
position or the coupling constant of the CHNH resonances
(nor of the CHMe or Me doublets) so that one predominant
(у95%) conformer exists in these solvents with the amino
groups axial.
ϩ
ously7 and revealed that the NH3 groups occupied the equa-
torial sites.
Information on the preferred solution conformation of such
cyclohexyl derivatives may be gleaned by analysis of the H
1
1446
J. Chem. Soc., Perkin Trans. 2, 1997

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Reaction chemistry
S
Reaction of 2a with ethyl bromoacetate in dimethylformamide
(DMF ) in the presence of caesium carbonate afforded the tri-
ester 8 in 83% isolated yield after purification by chroma-
tography on neutral alumina. The buttressing methyl groups
inhibit alkylation of the secondary amine sites, explaining the
lack of polyalkylated products. Acid hydrolysis (6 mol dmϪ3
HCl, 110 ЊC, 18 h) gave the corresponding amino acid 9a, as a
hydrate of the trihydrochloride salt. Reductive alkylation of 2a
using benzaldehyde in ethanol followed by borohydride reduc-
tion gave the tri-N-benzyl derivative 9b and the analogous hexa-
dentate ligand 11 was prepared similarly via the yellow tris-
imine 10. Attempted reaction of 9b with ethyl bromoacetate in
ethanol (80 ЊC, 72 h) gave rise to no tertiary amine products and
the starting material was recovered unchanged. Such behaviour
is also consistent with the steric inhibition to SN 2 attack caused
by the introduction of the proximate methyl groups. Nucleo-
philic attack at an sp2 carbon centre is usually less prone to
steric inhibition, but attempted reaction of 9b with paraform-
aldehyde in the presence of MeP(OEt)2 [75 ЊC, anhydrous
tetrahydrofuran (THF ), 4 Å sieves] gave less than 10% of the
expected condensation product.
HN
HN
X
14 X = NCS
15 X = NH2
HO(O)MeP
PMe(O)OEt
PMe(O)OEt
N
+
N
N
N
H
N
HO(O)MeP
H
N
H3C
17
16
HO(O)MeP
NH
NH2
PMe(O)OH
HN
Sulfonylation of the triamine 2a was also subject to some
degree of control by the neighbouring methyl groups. In this
case it allowed the isolation of the ditosylamide derivative 12b.
18
NHTs
NHTs
X
The condensation reaction of 2a with freshly resublimed
paraformaldehyde in the presence of MeP(OEt)2 in boiling
THF 13 resulted in the formation of the tricyclic bis-aminal 16.
There are two remote stereogenic centres at phosphorus in this
product and the compound was isolated as an almost equi-
molar mixture of the two sets of diastereoisomers, i.e. (RR/SS)
and (RS/SR). In each chiral diastereoisomer the P atoms are
non-equivalent and four distinct 31P resonances were obtained
almost in a 1:1:1:1 ratio. Acid hydrolysis of the diester 16 gave
a mixture of two products whose constitution was established
by a combination of 2-D NMR methods. Analysis by 31P NMR
revealed two resonances (δP 36.8, 33.5 at pD 1.5) in an approxi-
mate ratio of 55:45. Electrospray mass spectral analysis of the
reaction mixture gave peaks at m/z 380 and 356 in positive ion
mode and correspondingly m/z 378 and 354 in negative ion
X
NH
X
X
12a X = NHTs
b X = NH2
HN
X
13a X = NHTs
b X = NH2
Thus reaction of 2a with three or more equivalents of TsCl
(THF, Et3N; Ts = p-MeC6H4SO2) afforded the tritosylamide
12a in 75% isolated yield after recrystallisation, whereas use of
1.8 equivalents of TsCl under the same conditions yielded the
ditosylamide 12b in 80% yield. The tritosylamide 12a was
also remarkably unreactive in attempted alkylation reactions.
Attempted alkylation with methyl iodide under a variety of
different reaction conditions (e.g. MeI–Cs2CO3–DMF–100 ЊC;
NaH, THF, MeI; MeI–Cs2CO3–EtOH; MeI–Et3N–MeCN; 3
equiv. NaOEt–EtOH then DMF–MeI) led to none of the tri-
methylated product being isolated. The ditosylamide 12b did
react selectively with alkyl halides at the free amino group: in
the presence of K2CO3 in acetonitrile, alkylation with p-
bis(bromomethyl)benzene yielded the tetratosylamide 13a and
subsequent detosylation using sodium in liquid ammonia gave
the hexamine 13b. From the stereochemical analyses obtained
with the N-benzylamine 9b and the parent triamine 2a, it is
likely that in non-polar solvents the hexamine will adopt the
conformation shown with the amino groups axial, and the para-
substituted benzyl group disposed in an anti-conformation.
When in the syn-conformation (not shown), the aryl group
effectively bridges two facially coordinating N3 donor sets
which are held in close proximity.
mode. One product gave resonances typical of an amidinium
+
group (NCHN: δC 154.0; δH 8.20) and in this same product
13C-DEPT and 1H NMR analysis revealed an N-Me group.
When the acid hydrolysis reaction was carried out in 6 mol
dmϪ3 DCl, 1H and 13C NMR analysis revealed that there was no
incorporation of the D-label into any of the CH, CH2 or CH3
resonances. Taken together, this information was consistent
with the formation of the bridged amidine 17. The second
product was the ‘expected’ hydrolysis product 18, characterised
by its mass spectral behaviour (m/z 356 [Mϩ ϩ 1]) by 2-D 13C/
1H analysis, and by the fact that it formed a 1:1 complex with
Cu2ϩ ions in water [λmax = 700 nm, ε = 90 dm3 molϪ1 cmϪ1; m/z
(ESMS) = 416 (Mϩ ϩ 1), 428 (M ϩ Naϩ)].
Formation of this pair of products may be rationalised in
terms of a mechanism involving intramolecular hydride trans-
fer to an iminium ion (Scheme 3). Protonation of 16 is likely to
be accompanied by ring-opening of the strained 1,3-diazine
boat conformer, with the nitrogen lone-pair anti to the breaking
C᎐N bond providing some assistance. In the resulting structure,
the ‘exo-anomeric’ effect 11 dictates that the lone-pair anti to the
C᎐N may labilise that bond with respect to acid-promoted
cleavage. Thus, considering the tertiary N lone-pair and not-
withstanding the acidic reaction conditions which will lead to
predominant protonation of the amine groups, protonation of
the antiperiplanar C᎐N bond yields a bis-iminium salt which
rapidly hydrolyses to afford the pentadentate ligand 18. Alter-
natively, using the lone-pair of the secondary nitrogen atom,
the antiperiplanar C᎐N bond is activated and attacks the prox-
imate iminium ion with formation of a different iminium ion
Neighbouring group effects
The juxtaposition of the amino groups in the ‘triaxial’ con-
former may be expected to lead to some unusual intramolecular
effects. Reaction of 2a with carbon disulfide in ethanol simply
led to formation of the monoisothiocyanate of the cyclic thio-
urea, 14. Basic hydrolysis of the isothiocyanate group gave the
corresponding mono-amine 15. Such transformations allow an
alternative strategy to selective N-tosylation in distinguishing
one amino site from the other two.
J. Chem. Soc., Perkin Trans. 2, 1997
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Table 1 Protonation equilibria for triamines (298 K, I = 0.1 mol dmϪ3
NMe4NO3)
Ligand
pK1
7.83
10.17
8.90
9.50
9.60
pK2
pK3
pK4
2a
6.73
8.66
7.40
7.14
8.06
5.15
7.17
5.95
5.92
6.45
2ba
2cb
9a
3.87
9cc
a
In 0.1 mol dmϪ3 KCI.3a,3b b In 0.1 mol dmϪ3 KNO3.14 c Values given are
the mean of 3 independent measurements (±0.03).
Me groups may occur only on deprotonation of the di-
protonated amine [H2a]2ϩ. However, this effect alone probably
does not explain the reduction in the protonation constants
seen in the second and third pKa values for which the con-
sequences of steric inhibition of solvation 15 probably provide a
satisfactory explanation.
Conclusions
The sterically buttressed triamine 2a adopts a preferred solu-
tion conformation which places the NH2 groups axial and
therefore in close proximity. In this orientation a favourable
intramolecular hydrogen-bonded array is established and a
favourable stabilising σC᎐H–σ*C᎐N interaction may occur which
1
has been suggested by a reduced H NMR coupling constant
between the axial proton (anti to the C᎐N bond) and the vicinal
equatorial proton. The proximate methyl groups sterically
inhibit solvation of the protonated forms and lead to a dimin-
ished reactivity of the amine in nucleophilic attack at both sp3
and sp2 centres. The C3-symmetric aromatic precursors and
derivatives thereof possessing ‘AB2’ functionality are poten-
tially interesting starting materials for dendrimer synthesis.
Scheme 3
Experimental
possessing a mirror plane. In this species (Scheme 3) one of the
nitrogen lone-pairs is likely to be trans and antiperiplanar to a
C᎐H bond. Intramolecular hydride transfer may then occur
generating the N᎐Me group, leading to formation of the
thermodynamically stable amidinium ion.
All reactions were carried out in apparatus that had been oven-
dried and cooled under argon. All solvents were dried using an
appropriate drying agent and water was purified from the ‘Pur-
ite’ system. Alumina refers to Merck Alumina activity II–III
that had been soaked in ethyl acetate for at least 24 h prior to
use. Silica refers to Merck silica gel F60 (230–400 mesh).
1H and 13C NMR spectra were obtained with a Bruker AC
250 operating at 250.13 and 62.90 MHz respectively, Varian
Gemini 200 operating at 200 and 50.1 MHz, respectively, Var-
ian XL 200 operating at 200.1 MHz and a Varian VXR 400S
operating at 400.1 MHz. All chemical shifts are given in ppm
relative to the residual solvent resonance and coupling con-
stants are in Hz.
Mass spectra were recorded on a VG 7070E, operating in
FAB, EIϩ or DCI ionisation modes as stated. Electrospray mass
spectra were recorded using a VG Platform (Fisons instru-
ments) operating in ESϩ mode or were performed by the
EPSRC Mass Spectroscopy service at Swansea. Accurate mass
spectroscopy was performed by the EPSRC Mass Spectroscopy
service.
Infra-red spectra were recorded on a Perkin-Elmer 1600 FT-
IR spectrometer as a thin film or KBr disc as stated. Ultraviolet
spectra were recorded on a UVIKON 930 spectrometer. Com-
bustion analysis was performed using an Exeter Analytical Inc
CE440 elemental analyser. Melting points were determined on
a Gallenkamp melting point apparatus and are uncorrected.
Potentiometric titrations were performed on a Molspin 1 cm3
auto titrator using a Corning semi-micro electrode to measure
the pH.
Protonation equilibria
The successive protonation constants for 2a were measured
under standard conditions, and are compared to reported
values for the related triamines 2b and 2c (Table 1). Similar data
were obtained for the amino acid 9a, and a comparison has
been made to pKa measurements obtained by Zompa on the
analogue 9c.3b The base strength of 2a is considerably lower
than that of the parent triamine 2b in aqueous solution. This
may simply reflect the steric inhibition to solvation of the con-
jugate acids [H2a]ϩ, [H22a]2ϩ and [H32a]3ϩ accorded by the
bulky methyl groups. It is entirely reasonable, on the basis of
coulombic repulsion, that the amino groups in the di- and tri-
protonated species of 2a adopt equatorial sites. 1H NMR
analysis of the free amine of CD3OD had revealed a triplet for
the axial CHN resonance at 2.85 ppm (J 3 Hz). Addition of one
equivalent of CF3CO2H caused this resonance to shift to 3.24
ppm and although the resonance was broadened, the coupling
pattern could still be discerned with J = 3.3(5) Hz. When an
excess of CF3CO2H was added, the triplet shifted up to 3.73
ppm and the coupling constant was 5.2 Hz. This behaviour is
consistent with the monoprotonated amine also preferring a
conformation which places the amino groups axial. The surpris-
ingly low first pKa may be accounted for by the disruption to the
ideal hydrogen-bonded network present in the free triamine
caused by protonation. Addition of one proton leaves two
favourable hydrogen-bonding interactions but introduces a
Measurement of pKa
ϩ
repulsive interaction between the NH3 group and one NH2
The ligand solution (3 cm3; 0.001 mol dmϪ3) was added to the
titration cell and the calibrated pH electrode placed into the
group. Relief of steric compression between the 1,3 syn-axial
1448
J. Chem. Soc., Perkin Trans. 2, 1997

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solution so that its frit was below the liquid surface. With the
solution temperature maintained at 25 ЊC and with efficient
stirring the base solution (NMe4OH, 0.05 mol dmϪ3) was
titrated (in increments of 0.002 cm3, time delay of 5 s). The pH
curve was analysed as previously described 16 to determine the
pKa values of the ligand.
1,3-Bis(benzylamino)-5-nitro-2,4,6-trimethylbenzene 7b
To a solution of the imine 7a (0.7 g, 1.92 mmol) in boiling
ethanol (25 cm3) was added excess sodium borohydride (2.0 g)
in ten equal portions over a period of 10 days. After removal of
solvent under reduced pressure, the residue was treated with
water (15 cm3) and extracted with dichloromethane (3 × 20
cm3). The combined extracts were washed with water (2 × 10
cm3), dried (K2CO3) and solvent removed under reduced pres-
sure to yield a yellow solid, 606 mg (85%), mp 92–93 ЊC; Found
(EIMS) 375.1946; C23H25N3O2 requires 375.1947; δH (CDCl3)
7.45 (10H, m), 4.16 (4H, s, CH2N), 3.38 (2H, br s, NH), 2.36
(3H, s), 2.23 (6H, s); δC(CDCl3) 152.13 (s), 145.46 (s), 139.65 (s),
128.72 (d), 127.90 (d), 127.57 (d), 125.56 (s), 115.32 (s), 53.33
(t), 13.87 (q), 12.82 (q); λmax/nm (EtOH) 340 (ε 1360 dm3 molϪ1
cmϪ1).
1,3,5-Triamino-2,4,6-trimethylbenzene 4
To a mixture of trinitromesitylene (11.6 g, 45.5 mmol) in eth-
anol (300 cm3) in a Parr hydrogenator vessel (1 dm3), was added
5% Pt on carbon catalyst (750 mg) and the mixture was
allowed to react with H2 (40 psi, 20 ЊC) for 3 days. After
removal of the catalyst by filtration through a 0.5 cm plug of
silica gel, the solvent was removed under reduced pressure and
the solid dried under high vacuum (0.1 mmHg) to yield a pale
yellow solid, 7.54 g (99%), mp 103–104 ЊC (Found: C, 65.2; H,
9.27; N, 2.44. C9H15N3 requires C, 65.4; H, 9.14; N, 2.54%);
δH (CDCl3) 1.99 (9H, s, Me), 3.52 (6H, s, NH2); δC(CDCl3) 10.69
(Me), 98.64 (C᎐Me), 140.86 (C᎐NH2); m/z (DCI) 165.1 (Mϩ).
1-Amino-3,5-bis(benzylamino)-2,4,6-trimethylbenzene 7c
To a suspension of 7b (1.2 g, 3.28 mmol) in absolute ethanol (80
cm3) was added 5% Pt on carbon (200 mg), and the mixture was
shaken under 2.5 atmospheres of H2 gas for 6 days. The catalyst
was removed by filtration through a thin (0.5 cm) layer of silica
gel and the solvent was reduced to one fifth of its original vol-
ume. After standing for 2 days, a colourless crystalline solid
was collected by filtration, washed with cold ethanol (3 × 5
cm3), and dried under vacuum (0.1 mmHg) to constant weight,
to yield the crystalline solid, 0.84 g (74%), mp 91–92 ЊC;
δH (CDCl3) 7.56–7.40 (10H, m, ArH), 4.13 (4H, s, CH2N), 3.50
(2H, br s), 3.25 (2H, br s, NH), 2.30 (3H, s), 2.29 (6H, s, Me);
δC(CDCl3) 144.53 (s, C᎐N), 142.08 (s, C᎐N), 128.76 (d), 128.25
(d), 127.44 (d), 114.46 (s, C᎐Me), 110.98 (s, C᎐Me), 54.23 (t,
CH2N), 12.79 (q), 12.40 (q); Found (EIMS) 375.2206;
C23H27N3 requires 345.2205.
1,3-Diamino-5-nitro-2,4,6-trimethylbenzene 6
A suspension of trinitromesitylene (7.8 g, 30.6 mmol) and 5%
Pt on carbon (600 mg) in ethanol (300 ml) was allowed to
react under H2 gas (40 psi) for 1 hour at room temperature. The
catalyst was removed by filtration through a 0.5 cm plug of
silica gel and the solvent evaporated to approximately one third
of its original volume. On standing for 4 h, orange crystals had
deposited which were collected by filtration, washed with cold
ethanol (2 × 10 cm3), and dried in vacuum to constant weight
to give an orange microcrystalline product (2.81 g, 47%), mp
169–170 ЊC; Found (EIMS) 195.1007; C9H13N3O2 requires
195.1008; δH (CDCl3) 2.09 (6H, s, CH3), 2.11 (3H, s, CH3), 3.76
(4H, br s, NH2); λmax/nm (EtOH) 290 (ε 3550 dm3 molϪ1 cmϪ1),
368 (825).
cis,cis-1,3,5-Triamino-2,4,6-trimethylcyclohexane 2a
A suspension of the 10% Rh–0.1% Pd on carbon hydrogenation
catalyst (200 mg) in sulfuric acid solution contained in a pres-
surised hydrogenation vessel (3 mol dmϪ3, 80 cm3) was treated
with H2 gas (3 atm) at room temperature for 1 h. A solution of
the amine 4 (2 g, 12.1 mmol) in sulfuric acid (25 cm3) solution
was added by cannula under argon and the mixture was con-
tinuously shaken in a Parr hydrogenator (3 atm H2, 20 ЊC, 10
days). Reaction progress was monitored towards the end of
this period by analysing a sample by 13C NMR spectroscopy,
inspecting the disappearance of the aromatic carbon signals.
The catalyst was removed by filtration and the solvent removed
under reduced pressure to leave a volume of ca. 30 cm3. To
this solution was added ethanol (30 cm3) and then sufficient
dichloromethane (ca. 15–20 cm3) to give a cloudy solution. On
standing, a salt precipitated which was collected by filtration
and dried under reduced pressure (0.1 mmHg, 40 ЊC), giving the
sulfate salt as a colourless solid, 4.6 g (82%); m/z (DCI) 174
(Mϩ) for the cis,cis-major isomer; δH (D2O, pD 1) 0.90 (9H, d, 3J
7.5, CHCH3), 2.30 (3H, br m, CHCH3), 3.38 (3H, br m,
NH2CH); δC(D2O, pD 1) 12.03 (s, CH3), 34.59 (d, CH), 54.12 (d,
CHN). The major cis,cis-isomer was separated as the sulfate
salt by crystallisation from warm water and 1.9 g was isolated.
The constitution and nature of this isomer has been established
by X-ray crystallographic analysis, as reported previously. The
sulfate salt of 7 (1.5 g, 3.2 mmol) was added to dilute aqueous
potassium hydroxide solution (pH 12, 25 cm3) and the solution
was extracted with dichloromethane (4 × 20 cm3). The com-
bined extracts were dried (K2CO3), filtered and solvent removed
under reduced pressure to leave a colourless solid, mp 68–70 ЊC
(0.4 g, 74% recovery); m/z (DCI) 171 (Mϩ); δH (CDCl3) 1.18 (9H,
d, 3J 7.3, CH3), 1.65 (3H, tq, CHCH3), 1.60 (6H, br s, NH2), 2.81
(3H, t, J 3.0, CHNH2). In CD3OD solution, addition of excess
CF3CO2H gave a triplet for the CHNH3ϩ resonance: δH 3.73 (t,
J 5.1 Hz). δC(CDCl3) 16.00 (q, CH3), 40.88 (d, CHCH3), 56.52
(d, CHN) (Found: C, 63.2; H, 12.0; N, 24.2. C9H21N3 requires:
C, 63.2; H, 12.3; N, 24.5%).
1,3,5-Tris(benzylideneamino)-2,4,6-trimethylbenzene 5a
A suspension of 4 (2.27 g, 13.7 mmol) and freshly distilled
benzaldehyde (7.3 g, 69 mmol) was heated at 50 ЊC under
reduced pressure (ca. 25 mmHg) for 45 min. The resultant
brown tar was dissolved in hot ethanol (100 cm3) and water was
slowly added to the solution until it became cloudy. The mix-
ture was cooled to 0 ЊC, and after standing for 4 h, a crystalline
precipitate was collected by filtration, washed with water
(3 × 10 cm3) and dried to constant weight (0.01 mmHg, 40 ЊC)
to afford a yellow crystalline product (4.37 g, 72%), mp 155–
156 ЊC; Found (EIMS) 429.2255; C30H27N3 requires 429.2255;
δ (CDCl ) 8.35 (3H, s, CH᎐N), 8.04 (6H, ortho H), 7.61 (9H,
᎐
H
3
m, ArH), 2.05 (9H, s, CH3); δC(CDCl3) 163.42 (d), 150.21
(s), 136.38 (s), 131.68 (d), 129.04 (d), 128.80 (d), 112.60 (s),
13.86 (q).
1,3-Bis(benzylideneamino)-5-nitro-2,4,6-trimethylbenzene 7a
The procedure used to prepare 5a was followed giving 7a as a
pale yellow crystalline solid in a 93% overall yield, mp 142–
143 ЊC; Found (EIMS) 371.1629; C23H21N3O2 requires
371.1634; δ (CDCl ) 8.22 (2H, s, CH᎐N), 7.93 (4H, m, ortho
᎐
H
3
ArH), 7.52 (6H, m, ArH), 2.07 (6H, s, CH3), 1.96 (3H, s, CH3);
δC(CDCl3) 164.60 (d), 151.59 (s), 150.48 (s), 135.68 (s), 132.28
(d), 129.13 (d), 128.95 (d), 119.47 (s), 114.09 (s), 14.12 (q), 13.24
(q).
1,3,5-Tris(benzylamino)-2,4,6-trimethylbenzene 5b
Compound 5a was hydrogenated using the conditions used for
the preparation of 4 (40 psi H2, 20 ЊC, 62 h). The product was
recrystallised from ethanol to yield a colourless crystalline
solid, mp 45 ЊC (Found: C, 82.4; H, 7.89; N, 9.40. C30H33N3
requires C, 82.7; H, 7.64; N, 9.65%); δH (CDCl3) 7.48–7.33
(15H, m), 4.12 (6H, s, CH2N), 2.80 (3H, br s, NH), 2.32 (9H, s);
δC(CDCl3) 145.16 (s), 140.64 (s), 128.75 (d), 128.24 (d), 127.44
(d), 118.28 (s), 53.81 (t), 13.34 (q). m/z (DCI) 435 (Mϩ).
J. Chem. Soc., Perkin Trans. 2, 1997
1449

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cis,cis-1,3,5-Tris(ethoxycarbonylmethylamino)-2,4,6-trimethyl-
cyclohexane 8
8.13 (3H, dd, 4Ј-H), 8.23 (3H, br s, 6Ј-H), 8.31 (3H, s, CH᎐N),
᎐
12.98 (3H, br s, OH).
To a solution of the triamine 2a (0.12 g, 0.7 mmol) in dry DMF
(2 cm3) under argon was added caesium carbonate (0.9 g, 2.8
mmol) and ethyl bromoacetate (0.25 cm3, 2.2 mmol) and the
suspension was heated overnight at 60 ЊC. After removal of
solvent under reduced pressure the residue was taken up in the
minimum volume of dichloromethane, filtered and purified
by chromatography on neutral alumina to yield a colourless
oil (Rf = 0.25, Al2O3, CH2Cl2), 0.25 g (83%) m/z (ESϩ) 430
(Mϩ ϩ 1); δH (CDCl3) 1.07 (3H, d, CH3), 1.16 (6H, dd, CH3),
1.19 (9H, t, OCH2CH3), 1.55 (2H, m, CHCH3), 1.70 (1H, m,
CHCH3), 2.35 (2H, t, J 3, CHNH), 2.40 (1H, t, J 3, CHNH),
3.30 (4H, s, CH2CO), 3.33 (2H, s, CH2CO), 4.10 (6H, q ϩ q,
CH2O); δC(CDCl3) 14.0 (2C, s, CH3), 17.5 (1C, s, CH3), 40.1
(1C, s, CHCH3), 41.5 (2C, s, CHCH3), 54.0 (1C, s, NCH2CO),
54.5 (2C, s, NCH2CO), 60.0 (2C, s, CHN), 60.5 (1C, s, CHNH),
64.0 (1C, s, OCH2), 64.5 (2C, s, OCH2); νmax/cmϪ1 (thin film),
3580 (br w, NH), 3319 (br m), 2977–2875 (CH), 1739 (s, CO),
1505 (m), 1465 (m), 1373 (m), 1333 (w), 1268 (m), 1201 (s,
COC), 1142 (s), 1077 (m), 1030 (m), 920 (w), 857 (w), 733 (w).
To a suspension of the imine 10 (80 mg, 0.13 mmol) in dry
ethanol (10 cm3) was added sodium borohydride (200 mg, 2.7
mmol) and the mixture was boiled under reflux for 16 h. After
removal of solvent under reduced pressure, the residue was
treated with water (10 cm3), the pH adjusted to >13 (KOH
pellet) and a yellow solid precipitated, which was collected by
filtration and dried under high vacuum (0.02 mmHg, 30 ЊC) to
give a yellow solid (0.07 g, 85%), mp >250 ЊC (Found: C, 57.4;
H, 5.95; N, 13.2. C30H36N6O9 requires C, 57.7; H, 5.77; N,
13.5%); δH (D2O, pD 10), 1.42 (9H, d, CH3), 2.96 (3H, m, CH),
3.46 (3H, br m, CHN), 4.38 (6H, s, CH2N), 6.90 (3H, d, 3Ј-H),
7.92 (3H, br d, 4Ј-H), 8.14 (3H, s, 6Ј-H); m/z (ESMS) 625
(Mϩ ϩ 1).
cis,cis-1,3,5-Tris(p-tolylsulfonylamino)-2,4,6-trimethylcyclo-
hexane 12a
To a solution of the triamine 2a (0.25 g, 1.4 mmol) in warm
tetrahydrofuran (15 cm3) was added triethylamine (0.45 g, 4.4
mmol) and freshly recrystallised toluene-p-sulfonyl chloride (1
g, 5.2 mmol) and the mixture was boiled under reflux for 4 h.
After cooling to room temperature, the precipitate was removed
by filtration and solvent was removed under reduced pressure.
The solid residue was taken up in dichloromethane (20 cm3)
and washed successively with dilute aqueous hydrochloric acid
(2 × 10 cm3), dilute aqueous sodium hydroxide solution (2 × 10
cm3) and water (2 × 10 cm3). After drying (K2CO3) and filter-
ing, solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel, eluting
with hexane–dichloromethane (1:2, v/v; Rf 0.5). The resulting
solid was recrystallised from dichloromethane–hexane (ca. 1:3)
to give a colourless solid, 0.7 g (75%) (Found: C, 56.8; H, 6.33;
N, 6.54. C30H39N3S3O3 requires C, 56.8; H, 6.20; N, 6.63%);
δH (CDCl3) 0.54 (9H, d, 3J 7, CHMe), 1.71 (3H, m, CHMe), 2.46
cis,cis-1,3,5-Tris(carboxymethylamino)-2,4,6-trimethyl-
cyclohexane 9a
A solution of the triester 8 (0.23 g, 0.53 mmol) in hydrochloric
acid (6 mol dmϪ3, 3 cm3) was boiled under reflux (110 ЊC, 18 h).
After removal of the solvent under reduced pressure and pro-
longed drying (0.1 mmHg, 40 ЊC), a colourless salt was
obtained (0.24 g, 89%); m/z (ESϪ) 344 (Mϩ Ϫ 1); (ESϩ) 346
(Mϩ ϩ 1); δC(D2O, pD 1.5), 9.50 (CH3), 29.80 (CHCH3), 31.00
(CHCH3), 45.21 (NCH2), 58.14 (CHN), 168.03 (CO) (Found:
C, 34.89; H, 7.01; N, 8.04. C15H27N3O6ؒ3HClؒ3H2O requires C,
35.39; H, 7.08; N, 8.25%); νmax/cmϪ1 (Nujol) 3354 (br s, OH,
NH), 1731 (s, CO), 1566 (m), 1207 (s), 939 (m), 821 (s); δH (D2O,
pD 2), 1.16 (9H, d ϩ d, CH3), 2.59 (1H, br m, CHCH3), 2.72
(2H, br m, CHCH3), 3.54 (3H, t ϩ t, CHN), 3.90 (4H, s,
CH2CO), 4.00 (1H, br d, NCHCO), 4.09 (1H, br d, NCHCO).
3
(9H, s, CMe), 3.30 (3H, br m, CHNH), 5.46 (3H, d, J 5.5,
NHSO), 7.32 (6H, d, m-ArH), 7.68 (6H, d, o-ArH); δC(CDCl3)
15.83 (q, Me), 21.60 (q, ArMe), 38.82 (d, CHMe), 58.81
(d, CHN), 127.38 (d, meta), 129.77 (d, ortho) 137.5 (s, CMe),
143.9 (s, C᎐SO).
cis,cis-1,3,5-Tris(benzylamino)-2,4,6-trimethylcyclohexane 9b
To a solution of the triamine 2a (0.2 g, 1.1 mmol) in warm dry
ethanol (15 cm3) was added benzaldehyde (0.37 g, 3.3 mmol)
and the solution was boiled under reflux for 2 h. After removal
of solvent under reduced pressure, the residue was taken up in
dry ethanol (20 cm3) and solid excess sodium borohydride (250
mg) was added. The mixture was boiled under reflux for 2 h,
solvent evaporated under reduced pressure and the residue was
taken up in dry dichloromethane (2 × 5 cm3), filtered, dried
(K2CO2), filtered and solvent evaporated to yield a colourless
solid, 0.42 g (74%), mp 92–93 ЊC (Found: C, 81.5; H, 8.95; N,
9.51. C30H39N3 requires C, 81.6; H, 8.89; N, 9.57%); m/z (DCI)
cis,cis-1,3-Bis(p-tolylsulfonylamino)-5-amino-2,4,6-trimethyl-
cyclohexane 12b
Reaction of the triamine 2a with toluene-p-sulfonyl chloride
(1.8 equiv.) under the same conditions used to prepare 12a
gave rise to a colourless solid which was recrystallised from
dichloromethane–hexane (1:2 v/v), mp 136–138 ЊC (80%)
(Found: C, 57.3; H, 7.03; N, 8.42. C23H33N3O4S2 requires C,
57.6; H, 6.89; N, 8.79%); δH (CDCl3) 0.40 (3H, d, CH3), 1.10
(6H, d, CH3), 1.60 (2H, m, CHMe), 1.72 (1H, m, CHMe), 2.52
(6H, s, MeAr), 3.11 (1H, t, CHN), 3.50 (2H, t, CHN), 7.35 (4H,
d, CHAr), 7.72 (4H, d, CHAr); m/z (DCI) 479 (Mϩ), 480
(Mϩ ϩ 1).
3
442 (Mϩ); δH (CDCl3) 1.23 (9H, d, J 7, CHMe), 1.77 (3H, tq,
CHCH3), 2.61 (3H, t, J 3.1, CHNH), 3.40 (3H, br s, NH), 3.77
(6H, s, CH2N), 7.27 (15H, m, ArH); δC(CDCl3) 16.27 (q, Me),
41.35 (d, CH), 57.35 (d, CHN), 54.2 (CH2N), 126.27 (d, para),
127.71 (d, meta), 128.05 (d, ortho), 142.3 (s). This product did
not react with ethyl bromoacetate (EtOH, 80 ЊC, 72 h).
Synthesis of the tetratosylamide 13a
The substituted triamine 12b (0.24 g, 0.50 mmol) and potas-
sium carbonate (0.55 g, 4.0 mmol) were added to anhydrous
acetonitrile (15 cm3). α,αЈ-Dibromo-p-xylene (0.064 g, 0.25
mmol) was added and the mixture was stirred vigorously and
boiled under reflux for 12 h. The solvent was removed under
reduced pressure and the residue was partitioned between water
(20 cm3) and dichloromethane (20 cm3). The organic layer was
separated and dried with potassium carbonate. The solvent was
removed under reduced pressure and the resultant solid was
recrystallised from hexane–dichloromethane to give a colour-
less crystalline solid (0.2 g, 90%), mp 100–102 ЊC; δH (CDCl3)
cis,cis-1,3,5-Tris(2-hydroxy-5-nitrobenzylamino)-2,4,6-trimethyl-
cyclohexane 11
To a solution of 5-nitrosalicylaldehyde (168 mg, 1.05 mmol) in
ethanol (2 cm3) was added a suspension of the triamine 2a (60
mg, 0.35 mmol) in ethanol (1.5 cm3). The mixture was boiled
under reflux to yield a clear yellow solution after 5 min and
after a further 15 min a yellow solid began to precipitate from
the solution. After a total of 2 h, the mixture was cooled to
room temperature and the yellow solid collected by filtration,
washed with cold ethanol (3 × 3 cm3) and dried under vacuum
(0.1 mmHg, 20 ЊC) to give the intermediate tris-imine 10 as a
microcrystalline yellow solid; δH (CDCl3) 1.00 (9H, d, CH3),
2.52 (3H, m, CHMe), 3.53 (3H, t, CHN), 6.80 (3H, d, 3Ј-H),
3
3
0.25 (6H, d, J 7.5, CH3), 0.92 (12H, d, J 7, CH3), 1.69 (6H,
m, CHMe), 2.40 (12H, s, Me᎐Ar), 2.65 (2H, br, N᎐CH), 3.31
(4H, br, N᎐CH), 3.66 (4H, br, CH2Ar), 7.23 (12H, m, CHAr),
7.59 (8H, d, CHAr); δC(CDCl3) 15.76 (s, 2C, CH3), 16.4 (s, 4C,
1450
J. Chem. Soc., Perkin Trans. 2, 1997

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CH3), 21.5 (s, 4C, ArCH3), 39.2 (s, 2C, CH᎐CH3), 39.7 (s, 4C,
CH᎐CH3), 55.9 (s, 2C, CHN), 59.1 (s, 4C, CHN), 62.65 (s, 2C,
CH2), 126.9 (s, 8C, meta), 128.65 (s, 4C, Ar), 129.5 (s, 8C,
ortho), 138.32 (2C, CH2᎐Ar᎐C), 143.05 (4C, C᎐S) (Found: C,
61.23; H, 6.85; N, 7.92. C54H72N6S4O8 requires C, 61.16; H,
6.83; N, 7.91%); m/z (ESϩ) 1061.16 (Mϩ ϩ 1), 1062.15
(Mϩ ϩ 2), 1063.10 (Mϩ ϩ 3), 1082.9 (Mϩ ϩ 23), 1084.09
(Mϩ ϩ 24), 1085.13 (Mϩ ϩ 39), 1101.05, 1115.9; m/z (ESϪ)
1056.75, 1058.63, 1059.65, 1060.85, 1061.85, 1062.91, 1063.88.
was added a solution of diethoxy(methyl)phosphine (114 mg,
0.831 mmol) in diethyl ether (1.3 cm3), followed immediately by
paraformaldehyde (41 mg, 1.38 mmol). The solution was boiled
under reflux overnight with azeotropic removal of water using
4 Å molecular sieves. Removal of the solvent under reduced
pressure yielded a colourless viscous oil. Purification of the
product (Rf 0.8 on alumina using 10% methanol in dichloro-
methane) was effected using neutral alumina eluted with a sol-
vent gradient (0 to 3% methanol in dichloromethane) over a
period of 9 h to yield the product (51 mg, 60%) as a colourless
oil; δP(CDCl3) 54.72, 54.10, 52.47, 51.62; δH (CD2Cl2) 1.18
(1.5H, t, OCH2CH3), 1.22 (9H, CH3 ring), 1.28 (4.5H, 3 × t,
OCH2CH3), 1.45 (1H, br, CHCH3), 1.52 (3H, d, J 14, PMe),
1.53 (1.5H, d, J 14, PMe), 1.55 (1.5H, d, J 14, PMe), 1.81 (2H,
q, CHCH3), 2.45 (1H, s, CHN), 2.54 (1H, s, CHN), 2.78–2.96
(2H, m, NCH2P), 3.00–3.13 (2H, m, NCH2P), 3.18 (1H, s,
CHN), 3.77, 3.80, 3.92, 3.95 (4H, NCH2N), 3.9–4.1 (4H, m,
OCH2); δC(CD2Cl2) 12.91 (0.5C, d, J 90, PMe), 12.95 (0.5C, d,
J 90, PMe), 13.25 (1C, d, J 89, PMe), 16.84, 16.89, 16.98
(3C, OCH2CH3), 21.09 (3C, CHCH3), 44.5 (3C, CHCH3), 56.36
[1C, CHN(CH2)2], 58.13 (0.5C, d, J 114, NCH2P), 58.28 (0.5C,
d, J 113, NCH2P), 58.96 (0.5C, d, J 116, NCH2P), 59.08 (0.5C,
d, J 116, NCH2P), 68.24 (0.5C, d, J 13, HCNCH2P), 68.43
(0.5C, d, J 13, HCNCH2P), 68.84 (0.5C, d, J 13, HCNCH2P),
68.94 (0.5C, d, J 14, HCNCH2P), 70.27, 70.28 (d ϩ d, J 12,
NCH2N), 70.44 (1C, NCH2N); m/z (DCI) 436.2417 (Mϩ ϩ 1),
C19H40N3O4P2 requires 436.2417.
Synthesis of the hexamine 13b
To a solution of the tetratosylamide 13a (0.20 g, 0.18 mmol) in
tetrahydrofuran (20 cm3) and ethanol (2 cm3) held under argon
at Ϫ78 ЊC was added liquid ammonia (75 cm3). To this mixture
was added sodium metal (0.20 g), and the blue solution was
stirred for 2 h. The dark blue solution was then allowed to
warm up to room temperature while boiling off the ammonia.
Ethanol (2 cm3) followed by water (60 cm3) were added to the
residue and the organic solvents were removed under reduced
pressure. The pH of the solution was lowered to 1 using conc.
hydrochloric acid, and the aqueous solution was washed with
diethyl ether (3 × 30 cm3). The pH was raised to 12 (addition of
6 mol dmϪ3 KOH solution) and the solution was extracted with
dichloromethane (3 × 30 cm3). The solvent was removed under
reduced pressure to give a colourless solid (60 mg, 72%)
(Found: C, 70.24; H, 10.9; N, 18.77. C26H48N6 requires C,
70.27; H, 10.81; N, 18.91%); δH (CDCl3) 1.78 (18H, m, CH3),
1.63–1.69 (16H, m, CHMe, NH2, NH), 2.56 (2H, br, CH᎐NH),
2.75 (4H, br, CH᎐NH2), 3.70 (4H, s, CH2), 7.24 (4H, s, Ar);
δC(CDCl3) 16.11 (2C, s, CH3), 16.45 (4C, s, CH3), 41.02 (2C, s,
CH᎐CH3), 41.55 (4C, s, CH᎐CH3), 56.73 (4C, s, CH᎐NH2),
57.17 (2C, s, CH᎐NH), 63.55 (2C, C, CH2), 127.79 (4C, s,
Ar᎐C), 140.01 (2C), 63.55 (s, Ar᎐C); m/z (DCI) 444 (Mϩ), 445
(Mϩ ϩ 1).
Acid hydrolysis of 16
The phosphinate ester 16 (50 mg, 0.11 mmol) was dissolved in 6
mol dmϪ3 HCl (10 cm3), and the solution boiled under reflux for
18 h (110 ЊC). Water was removed under reduced pressure and
a colourless solid was obtained. Spectral analysis revealed an
approximately 1:1 mixture of the amidine salt 17, and the
amino acid 18; m/z (ESMS): compound 17 (ϩve): 380, (Ϫve)
378; C15H32N3O4P2 requires 380; compound 18 (ϩve): 356;
(Ϫve) 354; C13H31N3O4P2 requires 355; δP(pD 1.5) 36.8, 33.5;
δH (pD 1.5): compound 17: 8.20 (1H, s, NCHN), 3.93 (dd, 2H,
NCH2P), 3.80 (dd, 2H, NCH2P), 3.61 (br t, 2H, CHN), 3.53 (t,
1H, CHN), 2.82 (dq, 1H, CHMe), 2.66 (dq, 2H, CHMe), 2.57
(s, 3H, NMe), 1.28 (d, 6H, PMe), 1.15 (t, 9H, Me); compound
18: 3.61 (br m, 2H, CHN), 3.27 (t, 1H, CHN), 3.20 (d, 4H,
NCH2P), 2.40 (m, 2H, CHMe), 2.18 (q, 1H, CHMe), 1.28
(d ϩ d, 9H, Me), 0.80 (d, 6H, PMe); δC(pD 1.5): compound 17:
154.03 (NCHNϩ), 61.91 (2C, CHN), 55.20 (d, J 88, NCH2P),
51.40 (1C, CHN), 40.25 (CHMe), 38.40 (NMe), 30.81 (2C,
CHMe), 29.34 (1C, CHMe), 15.93 (1C, Me), 14.72 (d, J 94,
PCH3), 13.42 (2C, Me); compound 18: 63.54 (1C, CHN), 59.59
(2C, CHN), 43.46 (d, J 86, NCH2P), 40.25 (2C, CHMe), 31.48
(1C, CHMe), 14.44 (d, J 100 Hz, PMe), 9.33 (Me). 13C NMR
The cyclic thiourea-isocyanate 14
To a solution of the triamine 2a (80 mg, 0.47 mmol) in dry
ethanol (4 cm3) was added carbon disulfide (0.25 cm3, 4.2
mmol). A white precipitate appeared after 10 min. After boil-
ing the solution under reflux for 5 h, during which time H2S
evolution occurred, the solution was cooled, solvent removed
under reduced pressure and after drying in vacuum (0.02
mmHg, 35 ЊC) a colourless powder was obtained, 90 mg (75%),
mp 236–237 ЊC (Found: C, 51.8; H, 7.17; N, 16.2%. C11H17N3S2
requires C, 51.8; H, 6.70; N, 16.5%); δH (CDCl3) 1.04 (3H, d, J
5.0, CH3), 1.25 (6H, d, J 5.0, CH3), 1.74 (1H, m, CHMe), 1.88
(2H, m, CHMe), 3.09 (2H, br s, CHN), 4.05 (1H, t, CHN), 6.95
(2H, br s, NH); δC(CDCl3) 15.8 (2C, s, CH3), 16.13 (1C, s, CH3),
32.4 (1C, s, CH᎐CH3), 41.12 (2C, s, CH᎐CH3), 55.58 (2C, s,
CHN), 59.14 (1C, s, CHN), 151 (1C, s, NC᎐S), 177.4 (C, s,
᎐
N᎐C᎐S); νmax/cmϪ1 (KBr) 3191 (s), 2123 (m, NCS), 2962 (s),
and H assignments were confirmed by DEPT and HETCOR
1
᎐ ᎐
1550 (s), 1523 (s), 1455 (m), 1336 (m), 1197 (s); m/z (CI,
spectra.
MeOH) 256 (Mϩ ϩ 1).
X-Ray crystallography
The cyclic thiourea-monoamine 15
The diffraction experiments were carried out at room temper-
ature, on a Rigaku AFC6S 4-circle diffractometer (5a) and a
Siemens SMART 3-circle diffractometer with a CCD area
detector (7c). An empirical absorption correction was applied
for 5a using TEXSAN software17 (on 36 ψ-scans of 1 reflection,
min./max. transmission 0.86/1.00). The structures were solved
by direct methods (SHELXS-86 programs18) and refined by
full-matrix least squares against F 2 of all data (SHELXL-93
software19). In 5a, the N(5), C(50) atoms and the adjacent
phenyl group are disordered over two positions, A and B, with
the occupancies refined to 55(1) and 45(1)%, respectively. These
atoms were refined with isotropic displacement parameters (Ph
ring as rigid body), other non-H atoms in 5a and 7c with aniso-
tropic ones. In 5a, all H atoms were treated as ‘riding’. In 7c,
amino-H were refined isotropically, Me groups refined as rigid
bodies, other H atoms treated as ‘riding’ (with refined Uiso).
A suspension of the isothiocyanate 14 (120 mg, 0.47 mmol) in
aqueous sodium hydroxide (5 mol dmϪ3, 5 cm3) was boiled
under reflux for 18 h. The cooled solution was extracted with
dichloromethane (4 × 20 cm3), the combined extracts dried
(K2CO3), filtered and solvent removed under reduced pressure
to yield a colourless solid (80 mg, 80%), mp 174–175 ЊC; m/z
(ESϪ) 212 (Mϩ Ϫ 1); m/z (ESϩ) 235 (Mϩ Ϫ 1 ϩ Naϩ);
δH (CDCl3) 1.09 (3H, d, CH3), 1.26 (6H, d, CH3), 1.87 (3H, m,
CHMe), 2.50 (2H, br, NH2), 2.99 (1H, t, J 3, CHN), 3.14 (2H,
br m, CHN), 7.46 (2H, br s, NH); νmax/cmϪ1 3182 (s), 2959 (s),
1550 (s), 1510 (s), 1454 (s), 1260 (w), 1190 (s), 1025 (w), 907 (w).
The tricyclic bis-aminal 16
To 1,3,5-trimethyl-2,4,6-triaminocyclohexane (36 mg, 0.208
mmol) in sodium-dried THF (15 cm3) at 110 ЊC under argon
J. Chem. Soc., Perkin Trans. 2, 1997
1451

View Article Online
Table 2 Crystal data for 5a and 7c
3 (a) R. F. Childers, R. A. D. Wentworth and L. J. Zompa, Inorg.
Chem., 1971, 10, 302; (b) L. J. Zompa, Inorg. Chem., 1971, 10, 2647;
(c) E. B. Heisher, A. E. Gebala, A. Levey and P. A. Tasker, J. Org.
Chem., 1971, 36, 3042.
Compound
5a
7c
Formula
C30H27N3
429.55
0.5 × 0.5 × 0.05
Yellow
Monoclinic
P21/c (No. 14)
11.425(3)
20.314(3)
10.901(4)
98.20(2)
2504(1)
25, 23–40
1.14
C23H27N3
345.48
4 (a) J. E. Bollinger, J. T. Mague, C. J. O’Connor, W. A. Banks and
D. M. Roundhill, J. Chem. Soc., Dalton Trans., 1995, 1677;
J. E. Bollinger, J. T. Mague, W. A. Banks, A. J. Kastin and D. M.
Roundhill, Inorg. Chem., 1995, 34, 2143; (b) K. Hegetschweiler,
M. Ghisletta, T. F. Fassler, R. Nesper, H. W. Schmalle and G. Rihs,
Inorg. Chem., 1993, 32, 2032; K. Hegetschweiler, A. Egli, R. Alberto
and H. W. Schmalle, Inorg. Chem., 1992, 31, 4027.
Molecular weight
Crystal size/mm
Colour
Crystal system
Space group
a/Å
0.34 × 0.28 × 0.22
Light green
Monoclinic
P21/c (No. 14)
11.575(1)
17.152(2)
10.250(1)
106.09(1)
1955.0(5)
442, 10–23
1.18
Mo-Kα
0.710 73
0.7
ω (0.3Њ frames)
51
b/Å
c/Å
5 R. D. Hancock, Chem. Rev., 1989, 89, 1893.
6 K. Hegetschweiler, M. Ghisletta, L. Hausherr-Primo, T. Kradolfer,
H. W. Schmalle and V. Gramlich, Inorg. Chem., 1995, 34, 1950.
7 S. de Angelis, A. Batsanov, T. J. Norman, D. Parker, K. Senanayake
and J. Vepsalainen, J. Chem. Soc., Chem. Commun., 1995, 2361.
8 E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley–Interscience, New York, 1994, p. 696.
9 D. S. Kemp and K. S. Petrakis, J. Org. Chem., 1981, 46, 5140;
K. Williams, B. Askew, P. Ballester, C. Buhr, K. S. Jeong, S. Jones
and J. Rebek Jr., J. Am. Chem. Soc., 1989, 111, 1070.
10 A. Cahours, Ann. Chim. (Paris), 1849, 25, 40; A. W. Hoffmann,
Annalen, 1849, 71, 129; N. A. Kholevo, Zh. Prokl. Khim (Lenin-
grad), 1930, 3, 251.
11 P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon Press, Oxford, 1983; A. J. Kirby, The Anomeric Effect and
Related Stereoelectronic Effects at Oxygen, Springer-Verlag, Berlin,
Heidelberg and New York, 1983.
12 D. Hofner, S. A. Lesko and G. Binsch, Org. Magn. Reson., 1978,
11, 179.
β/Њ
V/Å3
Setting reflections, θ/Њ
Dx/g cmϪ3
Radiation
Cu-Kα
1.541 84
5.2
2θ/ω
150
-
λ/Å
µ/cmϪ1
Scan mode
Max. 2θ/Њ
Data total, unique, R(int)
Data observed, I > 2σ(I )
Number of least squares
variables
R (F, obs. data)
wR (F2, all data)
Goodness-of-fit
Max, min ∆ρ/e ÅϪ3
3975, 3516, 0.023 8650, 3215, 0.038
1925
259
1938
268
0.067
0.208
1.02
0.21, Ϫ0.25
0.050
0.146
1.10
0.14, Ϫ0.14
13 E. Cole, C. J. Broan, K. J. Jankowski, D. Parker, K. Pulukkody,
B. A. Boyce, N. R. A. Beeley, K. Millar and A. T. Millican, Syn-
thesis, 1992, 63.
14 K. Hegetschweiler, V. Gramlich, M. Ghisletta and H. Samaras,
Inorg. Chem., 1992, 31, 2341.
15 C. H. Rochester and B. Russell, J. Chem. Soc. B, 1967, 743;
H. Maskill, The Physical Basis of Organic Chemistry, Oxford
University Press, Oxford, 1989, p. 201.
16 G. B. Bates and D. Parker, J. Chem. Soc., Perkin Trans. 2, 1996,
1109.
17 TEXSAN, Version 5.0, TEXRAY Structure Analysis Package,
Molecular Structure Corporation, The Woodlands, TX77381, USA,
1989.
18 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
19 G. M. Sheldrick, SHELXL-93, Program for the Refinement of
Crystal Structures, University of Göttingen, Germany, 1993.
Crystal data and experimental details are listed in Table 2.
Atomic coordinates, bond lengths and angles, and thermal
parameters have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC). For details of the deposition
scheme, see ‘Instructions for Authors’, J. Chem. Soc., Perkin
Trans. 2, 1997, Issue 1. Any request to the CCDC for this
material should quote the full literature citation and the refer-
ence number 188/76.
We thank EPSRC, BBSRC for an equipment grant, and the
University of Kuopio, Finland (J. V.) for support.
References
1 M. Goodall, K. Gloe, P. M. Kelly, D. Parker and H. Stephan,
J. Chem. Soc., Perkin Trans. 2, 1997, 59.
2 (a) E. Swarzenbach, Helv. Chim. Acta, 1952, 35, 2344; (b) H. Stetter,
D. Thiesen and G. J. Steffens, Chem. Ber., 1970, 103, 200; L.
Fabbrizzi, M. Micheloni and P. Paoletti, J. Chem. Soc., Dalton
Trans., 1980, 1055.
Paper 7/01364G
Received 26th February 1997
Accepted 10th April 1997
1452
J. Chem. Soc., Perkin Trans. 2, 1997