Design and sterospecific synthesis of modular ligands based upon cis-1,3-trans-5-substituted cyclohexanes

Article abstract of DOI:10.1039/b503606b

A range of eight novel ligands, based on the cis-1,3-trans-5-substituted cyclohexane framework, have been synthesized by a stereospecific route starting from cw-1,3,5-cyclohexanetriol. This route depends on the use of efficient mono-silylation and mono-to

Full text of DOI:10.1039/b503606b

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P A P E R
Design and sterospecific synthesis of modular ligands based upon
cis-1,3-trans-5-substituted cyclohexanes
John Fielden, Joanna Sprott and Leroy Cronin*
University of Glasgow, Department of Chemistry, Joseph Black Building, University Avenue,
Glasgow, UK G12 8QQ. E-mail: L.Cronin@chem.gla.ac.uk
Received (in Durham, UK) 10th March 2005, Accepted 13th June 2005
First published as an Advance Article on the web 8th July 2005
A range of eight novel ligands, based on the cis-1,3-trans-5-substituted cyclohexane framework, have been
synthesized by a stereospecific route starting from cis-1,3,5-cyclohexanetriol. This route depends on the use
of efficient mono-silylation and mono-tosylation procedures, is well optimised, and due to isolation of the
diazido alcohol precursor cis-3,5-diazido-trans-hydroxycyclohexane readily allows the synthesis of a sizeable
family of related ligands via O-derivatisation. Such derivatisations allow systematic changes between various
coordinating, hydrogen bonding and lipophilic groups, allowing potential for this ligand system to be utilised
in supramolecular coordination chemistry.
Herein, we present synthetic routes to the novel ligands cis-
Introduction
3,5-diamino-trans-hydroxycyclohexane (cis,trans-DAHC) and
cis-1,3-dihydroxy-trans-5-aminocyclohexane (cis,trans-DHAC).
These ligands were designed with the aim of incorporating
heteroleptic donor sets while preserving the molecular shape of
trans-TACH. However, the route chosen to cis,trans-DAHC
has allowed a new family of ligands promising diverse and
interesting coordination chemistry.19
Development of novel ligand systems is an important problem
for inorganic and supramolecular chemists, as highlighted in
recent years by the use of ligand directed ‘‘rational design’’
strategies, where the choice of suitable rigid ligands can control
the shape and size of multimetallic complexes.1–3 Ligands play
an equally important role in other areas of coordination
chemistry; for example helping mimic protein environments,4
–7
adjusting the magnetism of multimetallic clusters,8 and
influencing the reactivity of complexes, including catalysts.9,10
Furthermore, ligand design can be used to control the inter-
molecular interactions between discrete complexes in the as-
sembly of supramolecular arrays.11,12
Results and discussion
An overview of the family of ligands and the routes used in
their synthesis is presented as an abridged reaction scheme in
Scheme 1. This family comprises the three diamines cis-3,5-
diamino-trans-hydroxycyclohexane (cis,trans-DAHC, 5), cis-
3,5-diamino-trans-methoxycyclohexane (cis,trans-DAMC, 7)
and cis-3,5-diamino-trans-tert-butyldimethylsilylanyloxycyclo-
hexane (cis,trans-DATC, 13); the diol cis-1,3-dihydroxy-trans-
5-aminocyclohexane (cis,trans-DHAC, 18); and the four tetra-
dentate/bisbidentate cis,trans-DAHC derivatives; malonic acid
bis-(cis-3,5-diaminocyclohexyl) ester (MADACE, 10), glutaric
acid bis-(cis-3,5-diaminocyclohexyl) ester (GADACE, 11), cis-
3,5-bis[(2-pyridinyleneamin]-trans-hydroxycyclohexane
(DDOP, 14), and cis-3,5-bis[6-methyl-2-pyridinyleneamin]-
trans-hydroxycyclohexane (DDMOP, 15). It can be seen that
synthesis of this wide range of products is greatly facilitated by
the possibility of performing imine condensations on the
amines without reacting the alcohols, and by use of the
precursor 4 as a ‘‘pro-amine’’ whereby the alcohol group can
be reacted prior to reduction of the azide to the amine.
The first target ligand, cis,trans-DAHC (5), was previously
synthesised, though not isolated, in 1972 as a by-product in the
synthesis of the cis-isomer from 3,5-dinitrophenol.20 Its diace-
tamide derivative co-crystallised with the diacetamide of the
third, trans-isomer in a combined overall yield of 25%.
Although the poor yield is counterbalanced the relatively low
cost of the 3,5-dinitrophenol precursor, this method was not
considered suitable owing to the difficulty of separating the
desired isomer. However, discovery in the literature of a highly
effective mono-TBDMS protection protocol for cis-1,3,5-cyclo-
hexanetriol (Scheme 2)21,22 inspired the use of a tosylation and
stereospecific, SN2 azide reaction to yield the desired cis,trans
While many large, frequently aromatic, ligands have been
synthesized for use in ligand directed strategies,1–3 rather less
attention has been paid to the design and synthesis of smaller,
non-aromatic building blocks. However, such ligands, by both
organic derivatisation and variation of complexation condi-
tions, can quickly provide access to a wide range of novel metal
complexes. One such example is provided by the two stereo
isomers of 1,3,5-triaminocyclohexane (cis-TACH and trans-
TACH), which have been used to synthesise a range of mono
and multinuclear coordination complexes,13–17 with further
variety yielded by the derivatisation of cis-TACH with carbox-
ylate donors.18 The trans-TACH ligand has proved particu-
larly interesting because of its combination of a potentially
chelating diamino ‘‘head’’ group with a non-interacting amino
‘‘tail’’ which may either coordinate or participate in hydrogen
bonding interactions. Furthermore, the coordination beha-
viour (chelating or bridging) of the diamine group appears
to be controlled by the nature of the metal centre; ‘‘closed
shell’’ d10 metal centres such as Ag(I) give bridged structures,
while ‘‘open shell’’ transition metals such as copper(II) prefer
chelation.
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 5
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Scheme 1 Abridged reaction scheme summarising the cis,trans-DAHC and cis,trans-DHAC ligand family.
diamino alcohol as the exclusive product in an overall yield of
69%. The extremely specific and high yielding nature of the
mono-TBDMS protection is vital to the viability of this route,
as it allows the tosylation and subsequent inversion of only two
of the three alcohols.
and water solubility eliminated the need for chromatographic
purification. The critical azide step to form 4 was performed
according to published methods,26 using a large excess of
sodium azide in DMF (CAUTION–azides can be explosive),
while the subsequent catalytic hydrogenation allowed isolation
of the target material 5 in adequate purity simply by filtration
of the catalyst.
In addition to efficiency, selectivity and synthetic ease, this
route has the advantage of isolating the diazido precursor 4.
The non-nucleophilic character of alkyl azides allows them to
act as ‘‘pro-amines’’, so that derivatisation of the alcohol group
can be performed without the need for protection and depro-
tection of the amine groups. In this way the methyl derivative
cis,trans-DAMC (7) could be obtained via a simple etherifica-
tion protocol,27 followed by hydrogenation.
Isolation of precursor 4 also opens the possibility of linking
two cis,trans-DAHC units to form a tetradentate ligand, with
the wide range of commercially available alkyl halides and
alkanoyl chlorides expected to allow a wide variety of lengths
and rigidities in the linker. While attempts to form a bis-ether
linkage failed due to elimination at the second centre, changing
to an ester linkage permitted the synthesis of MADACE (10)
and GADACE (11) by reaction with malonyl and glutaryl
dichloride respectively (Scheme 3). Relatively long reaction
times (48 h) were necessary in the initial esterification step,
while reduction of the resulting tetrazides proceeded better
using the more active Rh/C catalyst in place of Pd/C, perhaps
due to the presence of four, rather than two azide groups per
molecule. Ethanol and methanol proved to be the best solvents
despite the low solubility of the substrates in such polar
In the first, mono silylation step (Scheme 2) it was found that
extension of the published reaction time from 222 to 18 h was
necessary to achieve the published, or better than published,
yield of 1. The subsequent tosylation of the unprotected
alcohols was found to proceed best at low temperatures with
a relatively small excess (1.8 equivalents per alcohol) of recrys-
tallised tosyl chloride, giving a 95% yield of the desired bis-
tosylate 2. Larger quantities of tosyl chloride at higher tem-
peratures gave yields of only 40–70% due to a side reaction
forming the mono-chloro, mono-tosyl derivative trans-3-tert-
butyldimethylsilanyloxy-5-chlorotosyloxycyclohexane. Indeed,
direct conversion of alcohols to alkyl halides has been reported
in similar conditions.23 Removal of the TBDMS group to form
3 was carried out directly after the tosylation to avoid potential
problems with partial deprotection during the azide step,24
with an HF protocol25 being preferred to TBAF as its volatility
Scheme 2 Route to cis,trans-DAHC (5) and cis,trans-DAMC (7);
reagents, conditions and yields: (a) TBDMSCl, NEt3, NaH, THF, 40
1C, 20 h, 97%; (b) TsCl, pyridine, 0 1C, 48 h, 95%; (c); HF, CH3CN, 45
1C, 18 h, 95%; (d) NaN3, DMF, 70 1C, 24 h, 87%; (e) H2, Pd/C, EtOH,
rt, 18 h, 90%; (f) MeI, KOH, DMSO, rt, 6 h, 87%; (g) H2, Pd/C,
MeOH, rt, 20 h, 89%.
Scheme 3 Synthesis of MADACE (10) and GADACE (11); reagents,
conditions and yields: (a) malonyl/glutaryl dichloride, DMAP, DCM,
0 1C then rt, 48 h, 65%; (b) H2, Rh/C, EtOH, rt, 48 h, B90%.
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 1 5 2 – 1 1 5 8
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Scheme 4 Route to cis,trans-DATC, 13; reagents, conditions and
yields: (a) NaN3, DMF, 70 1C, 24 h, 77%; (b) (i) (Bu3Sn)2O, PMHS,
AIBN, n-PrOH, 85 1C, 2.5 h then HCl, 98%; (ii) NaOH, H2O, MeOH,
rt, 1 h, 66% (65% overall); or H2, Rh/C, MeOH, rt, 60 h, 93%.
solvents. When a 1 : 1 mixture of ethanol and ethyl acetate was
used to better dissolve the starting material, partly reduced
substrate would precipitate preventing complete reaction.
Having synthesised cis,trans-DAHC (5) and its methylated
analogue cis,trans-DAMC (7), the next logical step was to
derivatise the alcohol with a bulkier and more hydrophobic
group so that potential ligands with varying degrees of lipo-
philicity could be accessed. Consequently, the TBDMS deri-
vative cis,trans-DATC (13) was synthesised (Scheme 4). To
avoid unnecessary desilylation and resilylation of the oxygen,
only the first two steps of the route to 5 were followed. The
azide reaction was therefore performed on 2 resulting in a
slight loss of yield due to partial deprotection, with the target
material 12 being recovered in yields of 68 to 77%, and the
deprotected product 4 in a yield of around 15%. A similar
cleavage of methyldiphenylsilyl ethers at room temperature
with one equivalent of sodium azide in DMF has been docu-
mented,24 and although TBDMS ethers resisted these condi-
tions it appears that the higher temperatures and
concentrations of azide utilised here are capable of slowly
cleaving the TBDMS ether.
The following reduction step to yield 13 was also compli-
cated by the presence of the TBDMS protecting group. Poor
results were obtained using hydrogenation with Pd/C, which
has been shown to be capable of cleaving of silyl ethers.28
While a catalytic free radical reduction29 mediated by bis-
(tributyltin) oxide, AIBN, poly(methylhydrosiloxane)(PMHS)
and n-propanol gave satisfactory results, the acid work up is
likely to have caused some cleavage of the silyl group.30
Furthermore, a certain amount of product was lost in produ-
cing the free amine. Ultimately, the simplest and highest
yielding method proved to be hydrogenation with Rh/C as
the catalyst.
Scheme 6 Synthesis of cis,trans-DHAC, reagents, conditions and
yields: (a) n-BuLi, pyridine, TsCl, THF, 40 1C then rt, 15 h, 70%;
(b) NaN3, DMF, 70 1C, 16 h, 80%; (c) H2, Pd/C, EtOH, 18 h, 95%.
An alternative to derivatisation of the azide precursor 4 in
the synthesis of new cis,trans-DAHC based ligands is reaction
of the amines with aldehydes, for example 2-pyridinecarbalde-
hyde (Scheme 5). In this way, the bis-bidentate chelating
ligands DDOP (14) and DDMOP (15) can be synthesised by
a simple, high yielding procedure where cis,trans-DAHC is
refluxed in methanol with the appropriate aldehyde and 0.5
equivalents of triethylamine. A certain amount of unreacted
aldehyde remained which could not be removed owing to the
instability of imines to column chromatography, thus prevent-
ing the isolation of an analytical grade sample. However, the
presence of the aldehyde impurity is unlikely to cause signifi-
cant issues with complex formation.
The last ligand, cis,trans-DHAC (18), shares the same
geometry as cis,trans-DAHC (5) and trans-TACH, but the
bidentate chelating diamine group is replaced with a diol and
the trans substituent is an amine. The change of chelating
group is designed to adjust the coordination, hydrogen bond-
ing and solubility properties of the ligand. While derivatisation
of this molecule remains unexplored, the route through azido
diol 17 should provide similar possibilities to the cis,trans-
DAHC (5) synthesis for the generation of new, related ligands.
The synthesis of cis,trans-DHAC (Scheme 6) was ap-
proached in a similar way to that of DAHC, but in this case
inversion of only one of the substituents of cis-1,3,5-cyclohex-
anetriol was required. To this end it was necessary to develop a
monotosylation strategy, based on a literary precedent with a
large diol.31 This mono-tosylation of cis-1,3,5-cyclohexane triol
proceeds with reasonable selectivity, producing the desired
product in a 70% yield. Butyllithium is added prior to the
tosyl chloride in an effort to activate one alcohol towards
tosylation, but the selectivity is not nearly so impressive as
that seen in the mono-silylation, with bis and tris-tosylated
products also recovered during the chromatographic separa-
tion. Nonetheless, the ability to carry out a mono-tosylation,
albeit imperfectly, is essential to the viability of the route. The
subsequent azide reaction and catalytic hydrogenation are
essentially the same as the steps used in the synthesis of
cis,trans-DAHC (5). Overall, the efficiency of conversion of
cis-1,3,5-cyclohexane triol to cis,trans-DHAC is 53%.
Conclusions
The modular synthetic approach outlined above has so far
allowed access to eight different, novel ligands. It is to be
anticipated that many more may be synthesized via relatively
simple etherification, esterification, imination and amide form-
ing reactions. The cis,trans-DAHC and cis,trans-DHAC sys-
tems therefore represent a useful tool both for synthesis of new
Scheme 5 Synthesis of DDOP (14) and DDMOP (15). Yields are
calculated by H-NMR integration from impure material.
1
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coordination compounds, and studying the effect of systematic
changes in ligand substituents on complex size, shape and
properties. In addition, the cis,trans cyclohexane geometry,
as seen with TACH, provides an unusual angle between the
chelating and pendant groups, and hence should allow access
to interesting coordination and supramolecular chemistry, and
we are currently conducting investigations in these areas using
these ligands as a basis.
cis-1,3-Ditosyloxy-5-(tert-butyldimethylsilanyloxy)cyclohex-
ane (2). Tosyl chloride (19.41 g, 101.9 mmol) was added to a
solution of cis-(5-tert-butyldimethylsilanyloxy)cyclohexane-
1,3-diol (1) (6.942 g, 28.2 mmol) in distilled pyridine (70 ml),
with stirring at 0 1C. A change from a clear colourless solution
to an orange-pink suspension was observed. Stirring was
continued for 48 hours at 0 1C, before the suspension was
decanted into 100 ml water and 100 ml EtOAc and shaken. The
organic layer was recovered and washed with 3 ꢁ 80 ml
portions of brine, and the aqueous layer washed with 2 ꢁ 80
ml portions of EtOAc. The organic layers were combined and
reduced to ca. 50 ml on the rotary evaporator, before water
was added to precipitate the crude product overnight as a white
solid (14.775 g, 26.6 mmol, 94.5% yield after drying under
vacuum). NMR and MS showed that no further purification
was necessary for further reaction, a small sample was recrys-
tallised from acetone for melting point and elemental analysis.
Experimental
cis-1,3,5-cyclohexanetriol dihydrate (Aldrich/Fluka) was dried
under high vacuum (Schlenk line) at 50 1C. Tosyl chloride
(Lancaster) was recrystallised from ethyl acetate after washing
with 10% NaOH solution. THF (Fisher) was distilled over
sodium wire under nitrogen; pyridine (Lancaster) was distilled
and stored over NaOH under nitrogen; and triethylamine
(Lancaster) was distilled at reduced pressure over NaOH and
stored over NaOH under nitrogen. Water was purified with an
Elga Option 3 water purifier. Anhydrous DMF was supplied by
Aldrich. All other reagents and solvents (Fisher/Lancaster/
Riedel-de Haen/Avocado/Aldrich/BDH) and gases (BOC)
¨
were used as received. Deuterated solvents were obtained from
Aldrich, Avocado and Goss Scientific.
With the exception of the desilylations, hydrogenations and
O-methylation, all syntheses were carried out under an atmo-
sphere of calcium chloride dried oxygen-free nitrogen using
standard Schlenk techniques. TLC plates were developed using
an ultraviolet lamp, iodine chamber, KMnO4 dip (alcohols),
ninhydrin (amines), or phosphomolybdic acid in ethanol.
1
m.p. 112–114 1C. H-NMR (300 MHz, CDCl3): d 7.75 (d, 4H,
4ArH), 7.34 (d, 4H, 4ArH), 4.29 (ptpt, 2H, 2HCOTs), 3.40 (tt,
1H, HCOTBDMS), 2.47 (s, 6H, 2H3CAr), 2.17 (m, 1H, HCH
eq.), 1.99 (m, 2H, 2HCH eq.), 1.54 (pq, 1H, HCH ax.), 1.46 (pq,
2H, 2HCH ax.), 0.78 (s, 9H, TBDMS tert-butyl group), ꢀ0.08
(s, 6H, TBDMS methyl groups). 13C-NMR (100 MHz, CDCl3)
d: 145.1 (Ar, C), 134.0 (Ar, C), 130.0 (Ar, CH), 127.7 (Ar, CH),
74.3 (CH), 64.9 (CH), 41.0 (CH2), 37.8 (CH2), 25.6 (CH3), 21.7
(CH3), 18.0 (C), ꢀ4.9 (CH3). ES-MS: m/z 577.2, 578.2, 579.2 [M
þ Na]1; 405.1. IR (diamond anvil) cmꢀ1: 2955 m, 2936 m, 2858
m (CH); 1597 m, 1493 w (aromatic); 1342 s, 1173 s (-SO2–O);
1258 m (Si–C). Elemental analysis for C26H38O7S2Si, actual
(expected)%: C 56.21 (56.29), H 7.01 (6.90).
Kugelrohr sublimations were performed using a Buchi Glass
¨
Oven B-580. Melting points (given uncorrected) were recorded
with an Electrothermal IA 9000 digital melting point appara-
tus. NMR measurements were performed using Bruker DRX-
500 (500 MHz 1H, 2D experiments), DPX-400 and Avance-400
(400 MHz 1H, 100 MHz 13C, 2D experiments) and AC-300
(300 MHz 1H) spectrometers. Mass spectra were acquired with
LCT Micromass TOF (ES), Micromass Prospec (CI/EI) and
JEOL JMS-700 (FAB/CI/EI) mass spectrometers. Infra-red
measurements were taken using Shimadzu FTIR-8300 and
Jasco FTIR-410 spectrometers, and elemental analysis was
performed with an EA 1110 CHNS, CE-440 Elemental Ana-
lyser.
cis-3,5-Ditosyloxycyclohexanol (3). cis-1,3-ditosyloxy-5-(tert-
butyldimethylsilanyloxy)cyclohexane (2) (12.234 g, 22.05
mmol) was added to a 5% volume solution of 40% aqueous
HF in acetonitrile. After stirring for 17 hours at 40 1C, water
(150 ml) was added and the mixture extracted with chloroform
(3 ꢁ 150 ml). The combined organic layers were washed with
water (150 ml) and saturated brine (100 ml), before drying over
MgSO4 and evaporation of the solvent to yield the title
compound 3 (9.204 g, 20.9 mmol, 95%) as a white solid. A
small portion was recrystallised from hot Et2O/ethanol for
melting point and elemental analysis, yielding a white solid.
m.p. 127–129 1C. 1H-NMR (400 MHz, CDCl3): d 7.70 (d, 4H,
4ArH), 7.28 (d, 4H, 4ArH), 4.28 (ptpt, 2H, 2HCOTs), 3.49 (m,
1H, HCOH), 2.40 (s, 6H, 2H3CAr), 2.14 (m, 3H, 3HCH eq.),
1.53 (pq, 1H, HCH ax.), 1.37 (pq, 2H, 2HCH ax.). 13C-NMR
(100 MHz, CDCl3): d 145.2 (Ar, C), 133.8 (Ar, C), 130.0 (Ar,
CH), 127.6 (Ar, CH), 74.1 (CH), 64.4 (CH), 40.3 (CH2), 37.7
(CH2), 21.7 (CH3). FAB1-MS: m/z 441.1 [M þ H]1, 401.0,
360.2, 327.0, 281.0, 251.0, 207.0, 173.0 [TsOH2]1, 147.0, 97.4,
73.7. IR (KBr disc) cmꢀ1: 3428 s (OH); 2962 m, 2890 w (CH);
1599 m, 1496 w (aromatic); 1355 s, 1178 s (SO2–O); 1097 m (C–
O) Elemental analysis for C20H24O7S2, actual (expected) %: C
54.49 (54.53), H 5.51 (5.49).
Syntheses
cis-5-(tert-Butyldimethylsilanyloxy)cyclohexane-1,3-diol (1).
tert-Butyldimethylsilyl chloride (2.584 g, 16.6 mmol), followed
by NEt3 (1.68 g, 16.6 mmol), were added to a suspension of
anhydrous cis-1,3,5-cyclohexanetriol (1.999 g, 15.1 mmol) in
dry THF (40 ml). The mixture was stirred for half an hour
before the addition of one equivalent NaH (0.666 g, 60% in oil,
16.6 mmol), whereupon the suspension fizzed and evolved heat.
A temperature of ca. 45 1C was maintained for 2.5 hours, when
TLC showed the reaction to be incomplete. Heating and
stirring were continued for 18 h before the suspension was
cooled to 10 1C and filtered to remove sodium chloride. The
filtrate was evaporated and then triturated with 40 ml n-
hexane, affording the pure title compound 1 (3.613 g, 14.7
mmol, 96.7% yield) as a white solid. m.p. 122.7–125 1C (lit.
cis-3,5-Diazido-trans-hydroxycyclohexane (4). To cis-1,3-
ditosyloxy-5-hydroxycyclohexane (3) (11.985 g, 27.21 mmol)
in anhydrous DMF was added sodium azide (17.70 g, 272.3
mmol). The resulting suspension was stirred at 70 1C for 16
hours before cooling, addition of EtOAc (80 ml) and removal
of salts by filtration. The salts were washed with EtOAc, the
washings combined with the filtrate and washed with water
(3 ꢁ 80 ml), and the aqueous layer back extracted with EtOAc
(2 ꢁ 50 ml). Combination of the organic layers, drying over
MgSO4 and reduction on the rotary evaporator, followed by
column chromatography on silica (37.5% to 75% EtOAc in
hexane) afforded the title compound 4 as a pale yellow oil
(4.291 g, 23.6 mmol, 87% yield). 1H-NMR (400 MHz, CDCl3):
d 4.27 (m, 1H, HCOH), 3.70 (ptpt, 2H, 2HCN3), 2.23 (m, 1H,
1
value 120–122 1C). H-NMR (300 MHz, CDCl3): d 3.78 (m,
3H, 2HCOH þ HCOTBDMS), 2.28–1.93 (m, 5H, 3HCH eq. þ
2HOCH), 1.55 (m, 3H, 3HCH ax.), 0.89 (s, 9H, TBDMS tert-
butyl group), 0.08 (s, 6H, TBDMS methyl groups). 13C-NMR
(100 MHz, CDCl3) d: 67.1 (CH), 66.2 (CH), 42.7 (CH2), 42.5
(CH2), 25.8 (CH3), 18.1 (C), ꢀ4.8 (CH3). ES-MS: m/z 269.1 [M
þ Na]1. IR (diamond anvil) cmꢀ1: 3406 m, 3271 w, 3136 sh
(OH); 2928 m, 2858 m (CH); 1250 m (Si–C); 1099 s, 1045 s (C–
O). Elemental analysis for C12H26O3Si, actual (expected) %: C
58.36 (58.49), H 10.80 (10.63).
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 1 5 2 – 1 1 5 8
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HCH eq.), 1.99 (m, 2H, 2HCH eq.), 1.36 (ptd, 2H, 2HCH ax.),
1.28 (pq, 1H, HCH ax.). 13C-NMR (100 MHz, CDCl3): d 65.7
(CH), 54.1 (CH), 37.5 (CH2), 37.0 (CH2). EI1-MS: 182.2 [M]1,
179.1, 112.1, 93.0, 67.1, 55.1. IR (diamond anvil) cmꢀ1: 3383 m
(OH); 2933 m, 2903 sh, 2852 w (CH); 2083 vs., 1234 s (N3);
1126 s (C–O). Elemental analysis for C6H10N6O, actual (ex-
pected) %: C 39.42 (39.56), H 5.55 (5.53), N 45.21 (46.13).
dichlormethane (15 ml). After further stirring at 0 1C for 20
minutes, the ice bath was removed and reaction continued at
room temperature for 48 hours. Saturated sodium hydrogen
carbonate (20 ml) was added, the layers separated, and the
aqueous layer extracted with dichloromethane (2 ꢁ 20 ml). The
combined organic layers were then washed with water (2 ꢁ 20
ml) and saturated brine (20 ml) before drying over MgSO4 and
evaporation of solvent in vacuo. Column chromatography on
silica (20% EtOAc in hexane) yielded the title compound as a
pale yellow oil (0.382 g, 0.883 mmol, 67%). 1H-NMR (400
MHz, CDCl3): d 5.29 (t, 2H, 2HCOCOR), 3.58 (ptpt, 4H,
4HCN3), 3.32 (s, 2H, malonyl H2C), 2.32 (m, 2H, 2HCH eq.),
2.24 (m, 4H, 4HCH eq.), 1.44 (ptd, 4H, 4HCH ax.), 1.36 (pq,
2H, 2HCH ax.). 13C-NMR (100 MHz, CDCl3): d 165.2 (CO),
70.0 (CH), 54.1 (CH), 41.5 (CH), 36.5 (CH2), 34.5 (CH2). CI1-
MS: m/z 433.3 [M þ H]1, 405.2 [MH ꢀ N2]1, 362.2 [M ꢀ N5]1,
326.3, 269.2, 225.2, 199.2. 137.1, 94.1. IR (diamond anvil)
cis-3,5-Diamino-trans-hydroxycyclohexane (5). To cis-3,5-
diazido-trans-hydroxycyclohexane (4) (0.611 g, 3.35 mmol) in
ethanol (20 ml) was added 10% Pd/C catalyst (0.025 g). The
mixture was agitated for 18 hours at 25 1C, under a hydrogen
atmosphere of 6 bar before the catalyst was removed by gravity
filtration. Evaporation of the solvent yielded 5 as a white solid
(0.393 g, 3.02 mmol, 90% yield). 1H-NMR (400 MHZ, D2O): d
4.17 (pqi, 1H, HCOH), 2.93 (ptpt, 2H, HCNH2), 1.95 (m, 1H,
HCH eq.), 1.83 (m, 2H, 2HCH eq.), 1.18 (ptd, 2H, 2HCH ax.),
0.88 (pq, 1H, HCH ax.). 13C-NMR (100 MHz, D2O): d 67.0
(CH), 43.7 (CH), 43.5 (CH2), 39.7 (CH2). CI1-MS: m/z 130.2
[M]1, 113.2 [M ꢀ OH]1, 97.1 [M ꢀ OH ꢀ NH2]1. IR (KBr
disc) cmꢀ1: 3346 s, 3282 w, 3176 sh (OH and NH2); 2925 s,
2853 sh (CH); 1609 s (NH2). Elemental analysis for the
dihydrochloride salt, C6H16Cl2N2O, actual (expected) %: C
34.98 (35.48), H 8.04 (7.94), N 13.50 (13.79).
cmꢀ1: 2952 w (CH ), 2087 vs. (N ), 1729 s (C O), 1249
Q
2
3
(N3), 1110 s (C–O).
Glutaric acid bis-(cis-3,5-diazidocyclohexyl) ester (9). cis-3,5-
Diazido-trans-hydroxycyclohexane (4) (0.504 g, 2.76 mmol)
and DMAP (0.170 g, 1.39 mmol) in dry dichloromethane (9
ml) were added dropwise over 30 minutes to a stirred, ice-
cooled solution of glutaryl dichloride (0.223 g, 1.32 mmol) in
dry dichloromethane (15 ml). After further stirring at 0 1C for
20 min, the ice bath was removed and reaction allowed to
proceed at room temperature for 4 days. Thin layer chromato-
graphy showed that the reaction was incomplete, so the reac-
tion mixture was refluxed for a further 24 hours. Saturated
sodium hydrogen carbonate (20 ml) was added, the layers
separated, and the aqueous layer extracted with dichloro-
methane (2 ꢁ 20 ml). The combined organic layers were then
washed with water (2 ꢁ 20 ml) and saturated brine (20 ml)
before drying over MgSO4 and evaporation of solvent in vacuo.
Column chromatography on silica (30% EtOAc in hexane)
yielded the title compound as a pale yellow oil (0.378 g, 0.821
mmol, 63%). 1H-NMR (400 MHz, CDCl3): d 5.21 (t, 2H,
2HCOCOR), 3.54 (ptpt, 4H, 4HCN3), 2.28 (t, 4H, 2 glutaryl
H2C), 2.07 (m, 6H, 6HCH eq.), 1.86 (qi, 2H, glutaryl H2C),
1.38 (ptd, 4H, 4HCH ax.), 1.31 (pq, 2H, 2HCH ax.). 13C-NMR
(100 MHz, CDCl3): d 171.6 (CO), 68.4 (CH), 54.2 (CH), 36.7
(CH2), 34.7 (CH2), 33.3 (CH2), 20.0 (CH2). CI1-MS: m/z 461.2
[M þ H]1, 433.2 [M þ H ꢀ N2]1, 390.2 [M ꢀ N5]1, 375.2
[M ꢀ H ꢀ 3N2]1, 297.2, 271.2, 242.2, 137.1, 94.1. IR (diamond
cis-3,5-Diazido-trans-methoxycyclohexane (6). To ground
KOH (1.16 g, 20.67 mmol) in DMSO (9 ml) was added cis-
1,3-diazido-trans-5-hydroxycyclohexane (4) (1.00 g, 5.49
mmol), followed by iodomethane (3.70 g, 26.06 mmol). The
mixture became brown and was stirred at room temperature
for six hours before it was poured into 30 ml water. This
yellow, cloudy aqueous mixture was extracted with dichloro-
methane (3 ꢁ 30 ml), the organic layers combined and washed
with water (2 ꢁ 60 ml) then brine (1 ꢁ 60 ml) before drying
over MgSO4 and removal of solvent in vacuo yielded the title
compound as a yellow oil (0.886 g, 4.52 mmol, 87% yield). 1H-
NMR (400 MHz, CDCl3): d 3.67 (m, 1H, HCOMe), 3.57 (ptpt,
2H, 2HCN3), 3.24 (s, 3H, H3COCH), 2.25 (m, 1H, HCH eq.),
2.17 (m, 2H, HCH eq.), 1.35–1.20 (m, 3H, 3HCH ax.). 13C-
NMR (100 MHz, CDCl3): d 74.3 (CH), 56.3 (CH3), 54.2 (CH),
36.9 (CH2), 34.2 (CH2). CI1-MS: m/z 197.2 [M þ H]1, 169.2
[MH ꢀ N2]1, 126.1, 109.1. IR (KBr disc) cmꢀ1: 2933 m, 2886
w, 2827 w (CH); 2082 vs. (N3), 1247 s (N3), 1081 s (C–O).
Elemental analysis for C7H12N6O, actual (expected) %: C
42.74 (42.85), H 6.18 (6.16), N 42.61 (42.85).
anvil) cmꢀ1: 2955 m, 2865 w (CH); 2094 s (N ), 1735 s (C O),
Q
3
1254 s (N3).
cis-3,5-Diamino-trans-methoxycyclohexane (7). cis-3,5-Diazi-
do-trans-methoxycyclohexane (6) (0.6 g, 0.003 mol) in metha-
nol (30 ml) was added to 10% Pd/C catalyst (0.07 g) and
hydrogenated (25 1C, 7 bar, 20 h). The reaction mixture was
filtered to remove the catalyst and the solvent removed in vacuo
producing the title compound as a yellow oil (0.39 g, 2.70
Malonic acid bis-(cis-3,5-diaminocyclohexyl) ester (MA-
DACE, 10). Malonic acid bis-(cis-3,5-diazidoocyclohexyl) ester
(8) (0.368 g, 0.85 mmol) in EtOH 1 : 1 EtOAc (20 ml) was
hydrogenated (25 1C, 7 bar) over 5% Rh/C catalyst (0.035 g),
with agitation, for 18 hours. Removal of the catalyst by
filtration and evaporation of solvent in vacuo afforded the title
compound as a sticky yellow solid (0.279 g, 0.850 mmol, 85%).
1H-NMR (400 MHz, CD3OD): d 5.24 (pqi, 2H, 2HCOCOR),
3.36 (s, 2H, malonyl H2C), 3.00 (ptpt, 4H, 4HCNH2), 2.09 (m,
6H, 6HCH eq.), 1.30 (ptd, 4H, 4HCH ax.), 1.04 (pq, 2H,
2HCH ax.). CI1-MS: m/z 329.2 [M þ H]1, 287.3, 231.2,
173.2, 131.2 (unassigned). IR (diamond anvil) cmꢀ1: 3272 m
(NH2), 2921 m (CH2), 1728 m (CO2R), 1585 s (NH2), 1244 m
(C–OR), 1140 m (C–OR).
1
mmol, 89% yield). H-NMR (400 MHz, D2O): d 3.70 (m, 1H,
HCOMe), 3.20 (s, 3H, H3COCH), 2.82 (ptpt, 2H, 2HCNH2),
1.98 (m, 2H, 2HCH eq.), 1.93 (m, 1H, HCH eq.), 1.08 (pdt, 2H,
2HCH ax.), 0.87 (pq, 1H, HCH ax.). 13C-NMR (100 MHz,
D2O): d 76.2 (CH), 55.10 (CH3), 43.6 (CH), 43.4 (CH2), 36.7
(CH2). CI1-MS: m/z 145.2 [M þ H]1, 113.2. IR (NaCl disc)
cmꢀ1: 3342 m (NH2), 2925 m (CH), 1571 (NH2), 1073 m (C–
O). Elemental analysis as dihydrochloride salt, C7H16Cl2N2O,
actual (expected) %: C 38.11 (38.72), H 8.67 (8.36), N 13.10
(12.90).
Glutaric acid bis-(cis-3,5-diaminocyclohexyl) ester (GA-
DACE, 11). Glutaric acid bis-(3,5-diazidocyclohexyl) ester
(11) (0.266 g, 0.578 mmol) in EtOH (40 ml) was hydrogenated
(25 1C, 7 bar H2) over 5% Rh/C catalyst (0.060 g), with
agitation, for 24 hours. Removal of the catalyst by filtration
and evaporation of solvent in vacuo afforded the title com-
Malonic acid bis-(cis-3,5-diazidocyclohexyl) ester (8). cis-3,5-
diazido-trans-hydroxycyclohexane (4) (0.505 g, 2.77 mmol) and
DMAP (0.170 g, 1.39 mmol) in dry dichloromethane (10 ml)
were added dropwise over 30 min to a stirred, ice-cooled
solution of malonyl dichloride (0.183 g, 1.30 mmol) in dry
1156
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 1 5 2 – 1 1 5 8

View Article Online
pound as a slightly yellow, highly viscous oil (0.190 g, 0.533
mmol, 92%). 1H-NMR (400 MHz, D2O): d 5.10 (pqi, 2H,
2HCOCOR), 3.00 (ptpt, 4H, 4HCNH2), 2.31 (t, 4H, 2 glutaryl
H2C), 2.00–1.87 (m, 6H, 6HCH eq.), 1.80 (qi, 2H, glutaryl
H2C), 1.20 (ptd, 4H, 4HCH ax.), 0.93 (pq, 2H, 2HCH ax.). 13C-
NMR (100 MHz, D2O): d 175.1 (CO), 71.0 (CH), 44.1 (CH),
38.4 (CH2), 36.5 (CH2), 33.4 (CH2), 19.9 (CH2). FAB1-MS: m/
2HCH eq.), 1.16 (ptd, 2H, 2HCH ax.), 0.90 (pq, 1H, HCH ax.),
0.78 (s, 9H, TBDMS tert-butyl group), 0.00 (s, 6H, TBDMS
methyl groups). 13C-NMR (100 MHz, MeOD): d 68.8 (CH),
46.4 (CH), 45.6 (CH2), 43.0 (CH2), 26.3 (CH3), 18.9 (C), ꢀ4.8
(CH3). FAB1-MS: m/z 245.2 [MH]1, 185.1, 73.7, 70.8. IR
(KBr disc) cmꢀ1: 3432 s (NH2); 2929 m, 2854 m (CH); 1574 m
(NH2),1257 m (Si–C), 1055 s (C–O).
z 357.2 [M þ H]1, 259.1, 131.1, 96.4. IR (NaCl disc) cmꢀ1
:
3356 m (NH2), 2927 m (CH2), 1725 (CO2R), 1572 s (NH2),
1260 m (C–OR), 1155 m (C–OR).
(b) Hydrogenation over Rh/C. A solution of cis-3,5-diazido-
trans-(tert-butyldimethylsilanyloxy)cyclohexane (12, 0.500 g,
1.69 mmol) in methanol (30 ml) was added to 5% Rh/C
(0.060 g) and hydrogenated at 7 bar, 25 1C, for 60 hours.
Removal of the catalyst by filtration and evaporation of the
solvent in vacuo isolated the title compound 13 as a white waxy
solid (0.384 g, 1.57 mmol, 93%).
cis-3,5-Diazido-trans-(tert-butyldimethylsilanyloxy)cyclohex-
ane (12). Sodium azide (2.72 g, 41.8 mmol) was added to cis-
1,3-ditosyloxy-5-tert-butyldimethylsilanyloxycyclohexane (2)
(2.259 g, 4.08 mmol) in anhydrous DMF (30 ml). The resulting
suspension was stirred at 70 1C for 24 hours before it was
allowed to cool and the salts were filtered off and washed with
ether. The filtrate and washings were combined and washed
with 3 ꢁ 20 ml portions of brine, and the brine washed with 2
ꢁ 20 ml portions of ether, before the organic layers were
combined, dried over MgSO4 and reduced on the rotary
evaporator. The target compound 12 was isolated as a pale
yellow oil (0.917 g, 3.09 mmol, 77%) by column chromato-
graphy on silica, using 5% ether in hexane as eluent. 1H-NMR
(500 MHz, CDCl3): d 4.26 (m, 1H, HCOTBDMS), 3.71 (ptpt,
2H, 2HCN3), 2.33 (dt, 1H, HCH eq.), 1.97 (d, 2H, 2HCH eq.),
1.36 (ptd, 2H, 2HCH ax.), 1.34 (pq, 1H, HCH ax.), 0.89 (s, 9H,
TBDMS tert-butyl group), 0.06 (s, 6H, TBDMS methyl
groups). 13C-NMR (100 MHz, CDCl3): d 66.2 (CH), 54.3
(CH), 38.1 (CH2), 37.0 (CH2), 25.7 (CH3), 17.9 (C), ꢀ5.0
(CH3). EI-MS: m/z 296 [M]1; 281 [M ꢀ CH3]1; 239 [M ꢀ
C4H9]1; 211 [(M ꢀ C4H9) ꢀ N2]1; 196 [(M ꢀ C4H9 ꢀ N2) ꢀ
CH3]1, 168 [(M ꢀ C4H9 ꢀ N2 ꢀ CH3) ꢀ N2]1, 141, 128, 115
[Si(CH3)2(C4H9)]1, 101, 82, 75 [(CH3)2SiOH]1, 59, 41. IR
(diamond anvil) cmꢀ1: 2952 m, 2932 m, 2855 m (CH); 2091
vs. (N3); 1250 vs. (N3 and Si–C); 1042 s (C–O). Elemental
analysis for C12H24N6OSi, actual (expected) %: C 49.10
(48.62), H 8.34 (8.17), N 27.57 (28.36).
cis-3,5-bis[(2-Pyridinyleneamin]-trans-hydroxycyclohexane
(DDOP, 14). A methanolic solution (2 ml) of 2-pyridinecar-
boxaldehyde (0.587 g, 5.48 mmol) was added to a solution of
cis-3,5-diamino-trans-hydroxycyclohexane (5) (0.300 g, 2.27
mmol) and triethylamine (0.115 g, 1.14 mmol) in methanol
(50 ml). The mixture was refluxed under nitrogen for 20 hours
and the volume was then reduced giving a brown oil. This was
extracted from water with chloroform (3 ꢁ 25 ml), the organic
layer back-extracted with water (3 ꢁ 25 ml) and dried over
MgSO4 before evaporation of solvent yielded 14 (0.685 g, 94%
pure by NMR, 2.09 mmol, 92% yield) as a brown oil. 1H-
NMR (400 MHz, CDCl3): d 8.58 (m, 2H, 2ArH), 8.41 (s, 2H,
2HC N), 7.92 (m, 2H, 2ArH), 7.67 (ptd, 2H, 2ArH), 7.24 (m,
Q
2H, 2ArH), 4.40 (pqi, 1H, HCOH), 3.90 (ptpt, 2H, 2HC-N),
2.01–1.80 (m, 6H, 3H2C). 13C-NMR (100 MHz, CDCl3): d
160.6 (HC N), 154.6 (Ar, C), 149.4 (Ar, CH), 136.6 (Ar, CH),
Q
124.8 (Ar, CH), 121.6 (Ar, CH), 66.6 (CH), 62.8 (CH), 41.09
(CH2), 39.70 (CH2). EI1-MS: m/z 308.2 [M]1, 202.1 [M ꢀ
C6N2H5]1, 183.1, 158.1, 119.0. IR (diamond anvil) cmꢀ1: 3278
m (OH); 2926 m, 2858 m (CH); 1643 s (C N); 1130 s (C–O).
Q
cis-3,5-bis[6-Methyl-2-pyridinyleneamin]-trans-hydroxycyclo-
hexane (DDMOP, 15). A methanolic solution (2 ml) of 2-
pyridinecarboxaldehyde (0.516 g, 4.26 mmol) was added to a
solution of cis-3,5-diamino-trans-hydroxycyclohexane (15)
(0.252 g, 1.94 mmol) and triethylamine (0.097 g, 0.97 mmol)
in methanol (50 ml). The mixture was refluxed under nitrogen
for 22 hours and the volume was then reduced giving a brown
oil. This was extracted from water with chloroform (4 ꢁ 20 ml),
the organic layer back-extracted with water (1 ꢁ 30 ml) and
dried over MgSO4 before evaporation of solvent yielded 15
(0.72 g, 89% pure by NMR, 1.92 mmol, 99% yield) as a brown
cis-3,5-Diamino-trans-(tert-butyldimethylsilanyloxy)cyclo-
hexane (13). (a) Free radical reduction. AIBN (0.050 g, 0.26
mmol), n-PrOH (1.738 ml, 23.25 mmol), PMHS (2.08 ml, 1.10
mmol) and (Bu3Sn)2O (0.150 ml, 0.29 mmol) were added to cis-
1,3-diazido-trans-5-tert-butyldimethylsilanyloxycyclohexane
(12) (1.733 g, 5.85 mmol). After 20 minutes stirring at 85 1C the
mixture started to bubble due to release of N2, and after 1 hour
the colour changed from yellow to black and the bubbling
slowed. After 2.5 hours the mixture was allowed to cool, before
addition of anhydrous HCl (2.0 M in ether, 10 ml) and a small
amount of hexane resulted in formation of a white precipitate.
This was washed with hexane and dried under vacuum to yield
the title compound 13 as the dihydrochloride salt (13a) (1.822
g, 5.74 mmol, 98.2% yield). 1H-NMR (400 MHz, D2O): d 4.35
(m, 1H, HCOTBDMS), 3.55 (ptpt, 2H, 2HCNH31), 2.28 (dt,
1H, HCH eq.), 2.00 (m, 2H, 2HCH eq.), 1.46 (ptd, 2H, 2HCH
ax.), 1.42 (pq, 1H, HCH ax.), 0.78 (s, 9H, TBDMS tert-butyl
group), 0.00 (s, 6H, TBDMS methyl groups). FAB1-MS: m/z
525.1 [(M þ H)2Cl]1, 321.0, 287.1, 245.1 [M þ H]1, 185.1,
73.3, 70.3. IR (KBr disc) cmꢀ1: 3434 s (NH31, water and
deprotected OH), 1612 (NH31), 1261 m (Si–C), 1068 m (C–O).
This dihydrochloride salt 13a (2.06 g, 6.48 mmol) in 130 ml
methanol was then treated with NaOH (1.20 g, 15.04 mmol)
and water (15 ml) and stirred until the cloudy mixture became a
clear solution. After reduction to dryness at the rotary eva-
porator, the title compound 13 (1.050 g, 4.30 mmol, 66%) was
recovered from the residue by Kugelrohr sublimation under
vacuum (high vac pump) in the temperature range 110–150 1C.
1H-NMR (400 MHz, D2O): d 4.23 (m, 1H, HCOTBDMS),
3.04 (ptpt, 2H, 2HCNH2), 1.94 (dt, 1H, HCH eq.), 1.81 (m, 2H,
oil. 1H-NMR (400 MHz, CDCl ): d 8.39 (s, 2H, 2HC N),
Q
3
7.74 (d, 2H, 2ArH), 7.56 (pt, 2H, 2ArH), 7.10 (d, 2H, 2ArH),
4.38 (pqi, 1H, HCOH), 3.88 (ptpt, 2H, 2HC–N), 2.52 (s, 6H,
H3CAr), 1.99 ꢀ 1.79 (m, 6H, 3H2C). 13C-NMR (100 MHz,
CDCl ): d 161.0 (HC N), 158.1 (Ar, C), 154.2 (Ar, C), 136.9
Q
3
(Ar, CH), 124.4 (Ar, CH), 118.6 (Ar, CH), 66.5 (CH), 62.7
(CH), 41.1 (CH2), 39.7 (CH2), 24.4 (CH3). EI1-MS: m/z 336.2
[M]1, 216.2 [M ꢀ C7N2H7 ꢀ H]1, 172.1, 147.1. IR (diamond
anvil) cmꢀ1: 3356 m (OH); 2925 m, 2860 m (CH); 1645 s (C
Q
N).
cis-1,3-Dihydroxy-5-tosyloxycyclohexane (16). To a suspen-
sion of anhydrous cis-1,3,5-cyclohexanetriol (1.855 g, 14.04
mmol) in dry THF (15 ml) was added n-butyllithium (2.5 M in
hexanes, 5.62 ml, 14.05 mmol). After stirring at 40 1C for 10
minutes dry pyridine (6.5 ml) was added, causing a colour
change to orange, and the suspension was stirred at 40 1C for a
further 30 minutes before cooling and addition of tosyl chlor-
ide (2.950 g, 15.47 mmol). The resulting clear brown solution
was stirred at room temperature for 15 hours, whereupon TLC
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 1 5 2 – 1 1 5 8
1157

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showed that all the tosyl chloride had been consumed. The
reaction was quenched with water, the mixture added to 20 ml
EtOAc and washed with 3 ꢁ 20 ml portions of water. The
aqueous layers were washed with 2 ꢁ 20 ml EtOAc and the
organic layers combined, dried over MgSO4 and reduced.
Purification by column chromatography on silica (1 : 1 EtOAc
/hexane, then 100% EtOAc, then 15% i-PrOH in EtOAc)
yielded the title compound 16 as an oily orange solid (2.832
g, 9.89 mmol, 70% yield). A small portion was recrystallised
from hot Et2O/EtOH, yielding a white crystalline solid for
melting point and elemental analysis. m.p. 94–97 1C. 1H-NMR
(400 MHz, CDCl3): d 7.71 (d, 2H, 2ArH), 7.26 (d, 2H, 2ArH),
4.40 (ptpt 1H, HCOTs), 3.60 (m, 2H, 2HCOH), 2.37 (s, 3H,
H3CAr), 2.10 (m, 3H, 3HCH eq.), 1.50 (pq, 2H, 2HCH ax.),
1.32 (pq, 1H, HCH ax.). 13C-NMR (100 MHz, CDCl3): d 144.9
(Ar, C), 134.0 (Ar, C), 130.0 (Ar, CH), 127.7 (Ar, CH), 75.8
(CH), 65.2 (CH), 42.4 (CH2), 40.2 (CH2), 21.7 (CH3). EI-MS:
m/z 286.2 [M]1, 245.1, 173.1 [TsOH2]1, 155.1 [Ts]1, 91.1, 73.1,
68.1. IR (KBr disc) cmꢀ1: 3340 s (OH); 2953 m, 2909 m (CH);
1599 m (aromatic); 1360 s, 1176 s (SO2–O). Elemental analysis
for C13H18O5S, actual (expected) %: C 54.38 (54.53), H 6.37
(6.34).
(KBr disc) cmꢀ1: 3342 s, 3273 m (OH and NH2); 2929 m, 2852
m (CH); 1626 m (NH2). Elemental analysis for C6H13NO2,
actual (expected): C 55.16 (54.94), H 10.15 (9.99), N 10.44
(10.68).
Acknowledgements
JF would like to thank the EPSRC for funding. JS worked on
this project as a 4th year undergraduate student in fulfilment of
the requirements for her MSci in Chemistry.
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(pdt, 2H, 2HCH eq.), 1.86 (dt, 1H, HCH eq.), 1.70 (dt, 1H,
HCH ax.), 1.60 (m, 2H, 2HCH ax.). 13C-NMR (100 MHz,
CDCl3): d 67.3 (CH), 52.6 (CH), 38.3 (CH2), 37.9 (CH2). CI1-
MS: m/z 158 [M þ H]1, 130 [MH ꢀ N2]1, 112 [M ꢀ N2 ꢀ
OH]1, 97, 79. IR (KBr disc) cmꢀ1: 3289 s (OH); 2941 m, 2854
8
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w
(CH); 2103 s, 1245 s (N3). Elemental analysis for
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C6H11N3O2, actual (expected) %: C 46.11 (45.85), H 7.105
(7.05), N 25.88 (26.73).
cis-1,3-Dihydroxy-trans-5-aminocyclohexane (18). A solution
of cis-1,3-dihydroxy-trans-5-aminocyclohexane (11) (0.359 g,
2.28 mmol) in ethanol (20 ml) was added to 10% Pd/C catalyst
(0.027 g). The mixture was agitated at 25 1C, under a hydrogen
atmosphere of 6 bar before the catalyst was removed by gravity
filtration. Evaporation of the solvent followed by a Kugelrohr
sublimation under high vacuum yielded 18 as a white solid
(0.285 g, 2.17 mmol, 95% yield). m.p. 146.5–148.5 1C. 1H-
NMR (400 MHz, D2O): d 3.97 (tt, 2H, 2HCOH), 3.31 (pqi, 1H,
HCNH2), 2.05 (m, 1H, HCH eq.), 1.70 (pdt, 2H, 2HCH eq.),
1.49 (m, 2H, 2HCH ax.), 1.33 (m, 1H, HCH ax.). 13C-NMR
(100 MHz, D2O): d 65.1 (CH), 43.7 (CH), 41.2 (CH2), 39.4
(CH2). CI1-MS: m/z 132.2 [M þ H]1, 114.1 [M ꢀ OH]1. IR
1158
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 1 5 2 – 1 1 5 8