Synthesis of water soluble O-glycosides of N-(hydroxyalkyl)-aminomethylferrocenes

Article abstract of DOI:10.1039/a908512b

A series of water soluble ferrocenylamine-glucose conjugates, [N-2-(p-D-glucopyranosyloxy)ethyl-, [N-3-(β-D-glucopyranosyloxy)propyl-, [B-5-(β-D-glucopyranosyloxy)pentyl-N-methylaminomethyl]ferrocene, has been synthesized from the methiodide salt of ./V.TV-dimethylaminomethylferrocene and N-(S.o-tri-O-benzyl-β-Dglucopyranosyloxy-ethyl, -propyl and -pentyl)amine respectively. W-Methylation of the products from the latter reaction was achieved by formylation followed by reduction with lithium aluminium hydride. Catalytic hydrogenolysis over palladium removed the benzyl protecting groups from the carbohydrate moiety to give the target conjugates. An alternative synthesis of [N-2-(β-D-glucopyranosyloxyethyl)aminomethyl]ferrocene using boron trifluoride-diethyl ether promoted glycosylation of penta-0-acetyl-D-glucopyranose and [A-(2-hydroxyethyl)N-methylaminomethyl]ferrocene followed by deacetylation of the carbohydrate protecting group using basic ion exchange resin was also developed. The pK, values of the water soluble conjugates were determined. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a908512b

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Synthesis of water soluble O-glycosides of N-(hydroxyalkyl)-
aminomethylferrocenes†
John S. Landells, Joy L. Kerr, David S. Larsen, Brian H. Robinson* and Jim Simpson
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand
Received 26th October 1999, Accepted 3rd March 2000
Published on the Web 7th April 2000
A series of water soluble ferrocenylamine–glucose conjugates, [N-2-(β--glucopyranosyloxy)ethyl-, [N-3-(β--
glucopyranosyloxy)propyl-, [N-5-(β--glucopyranosyloxy)pentyl-N-methylaminomethyl]ferrocene, has been
synthesized from the methiodide salt of N,N-dimethylaminomethylferrocene and N-(3,4,6-tri-O-benzyl-β--
glucopyranosyloxy-ethyl, -propyl and -pentyl)amine respectively. N-Methylation of the products from the
latter reaction was achieved by formylation followed by reduction with lithium aluminium hydride. Catalytic
hydrogenolysis over palladium removed the benzyl protecting groups from the carbohydrate moiety to give the
target conjugates. An alternative synthesis of [N-2-(β--glucopyranosyloxyethyl)aminomethyl]ferrocene using
boron trifluoride–diethyl ether promoted glycosylation of penta-O-acetyl--glucopyranose and [N-(2-hydroxyethyl)-
N-methylaminomethyl]ferrocene followed by deacetylation of the carbohydrate protecting group using basic ion
exchange resin was also developed. The pKa values of the water soluble conjugates were determined.
oxylate leaving groups cis to the Pt–C bond but internal
Introduction
aggravation was again evident with buffered aqueous injec-
In previous work we have shown the versatility of ferrocen-
tions.8 We therefore looked for alternative methodology which
ylamines as ligands for transition metals such as platinum().1
Reaction of FMA and PtCl2(DMSO)2 readily gives the cyclo-
metallated complex 1 which showed useful activity against
would allow us to use ferrocenylamines and their complexes as
bioprobes. Carbohydrates were attractive because they are
structurally diverse, generally neutral and water soluble. A
cisplatin, PtCl2(NH3)2, resistant tumours and low liver dysfunc-
range of compounds where the ferrocenyl group and sugar
tion.2 Unfortunately, it and a series of analogues did not offer
residues are linked via a heteroatom have been reported. These
significant advantages in comparison to other potential drugs.
include cyclodextrin complexes9 and ferrocene connected via
anomeric-O10 and -S11,12 and non-anomeric-O,-N11,13 linkages;
however many of these have low solubility in water. Altern-
atively, the ferrocenylsugar can be synthesized directly from
cyclopentadienyl C-glycosyls.7 There is one example where a
perbenzylated glucopyranosyl unit is attached to the Cp ring of
a ferrocene by a carbon–carbon bond.14 Although there are no
cytotoxicity data reported for these ferrocenylsugars, there is
an expectation that the pharmacological utility of the ferro-
cenylamines will be enhanced with a carbohydrate substituent
endowing them with greater water solubility.
Ferrocenylamines themselves exhibit biological activity.
Redox mechanisms have been proposed for metallocene anti-
tumour and drug activity3 and there is now strong evidence
that ferrocenium salts bind directly to DNA via preferential
interaction with the 5Ј-phosphate.4 Experimental data for ferro-
cenylamines and the cycloplatinated complexes are inconclusive
however. Their low oxidation potentials5,6 could allow in vivo
oxidation to the ferrocenium species but cell culture experi-
ments do not support this perception.7
If the efficacy of the ferrocenylamines and their metal com-
plexes is to be improved, it is desirable to probe the nature of
their in vivo and cellular interactions in an aqueous environ-
ment. Unfortunately, the hydrophobic character of the ferro-
cene compounds poses a problem for biological investigations.
Apart from solubility factors, hepatotoxicity and histology data
have shown2 that there is gross internal irritation from solids
with either non-aqueous or peanut oil intravenous injection in
mice. Increased aqueous solubility has been achieved in the
cyclometallated complexes by incorporation of anionic carb-
Our synthetic strategy was designed to lead to a general
preparation of water-soluble ferrocenylamine–carbohydrate
conjugates with functionalities which could be adapted for
co-ordination to PtII for studies on biological activity, directed
to specific protein interactions, or linked with metal clusters
and polyaromatic fluorophores to form ion-selective sensors.
This paper describes the synthesis of water soluble analogues of
FMA where one of the N-methyl groups has been replaced by
an alkyl substituent attached to a glucopyranosyloxy unit. The
following paper15 reports the syntheses and structures of
aminomethylferrocene–carbohydrate conjugates where a meth-
ylferrocene unit is attached to the nitrogen of the amine group
of an amino-sugar (i.e. the N-ferrocenyl-N-glycosyl amine).
The electrochemistry of both systems, N- and O-ferrocenyl-
amine glycosides, is also described in that paper.
Results and discussion
Three possible routes to ferrocenylamine–carbohydrate conju-
gates of type 2 based on the retrosynthetic bond disconnections
(A, B and C, Fig. 1) were investigated. It was envisaged that the
first, based on bond disconnection A, could be achieved using a
† Ferrocenylamine–carbohydrate conjugates. Part 1. Electronic sup-
plementary information (ESI) available: IR and 13C NMR data. See
http://www.rsc.org/suppdata/dt/a9/a908512b/
DOI: 10.1039/a908512b
J. Chem. Soc., Dalton Trans., 2000, 1403–1409
This journal is © The Royal Society of Chemistry 2000
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Fig. 1 Strategic bond disconnections.
Scheme 2
Scheme 1
modification of a reductive amination process developed by
Bernstein and Hall16 for the preparation of model glyco-
proteins. Our approach, outlined in Scheme 1, utilised an in situ
sodium cyanotrihydroborate reduction of the Schiff base
formed from the glucopyranosyloxyacetaldehyde 3 and ferro-
cenylamine 4 to link the carbohydrate and organometallic units.
Unfortunately, reaction of 3 and ferrocenylamine 4 under these
conditions gave a complex mixture of products, none of which
was identified as the target molecule 5. Similar problems were
encountered by Adam and Hall11 on attempted reduction of a
Schiff base derived from glucosamine 6 and ferrocenecarb-
aldehyde 7. These researchers succeeded in synthesizing a variety
of acetylated carbohydrate–ferrocene conjugates but attempts
to deacetylate the sugar moiety under basic conditions gener-
ally proved unsuccessful.
On the basis of the latter results, a strategy (using bond dis-
connection B) was developed which avoided the use of acetyl
protection of the carbohydrate and reductive amination pro-
cesses for coupling a ferrocene unit to the sugar. The synthetic
sequence, outlined in Scheme 2, relies on a nucleophilic substi-
tution reaction of O-glucosylated N-methylalkanolamines 8
with the methiodide salt 9 to provide the protected carbo-
hydrate–ferrocenylamine conjugate. The choice of benzyl (Bn)
protecting groups, which are easily removed by catalytic
hydrogenolysis, would circumvent inter- and intra-molecular
acyl transfer reactions which were presumably complicating the
chemistry described in Scheme 1.
Scheme 3
reported for coupling processes using benzylated glycosyl
donors. N-Hydroxyalkylphthalimides 12a to 12c were prepared
from the corresponding alkanolamine and phthalic anhydride.18
Their zinc chloride promoted glycosylations with the 1,2-
epoxide of tri-O-benzyl--glucal 13 afforded after silica-gel
column chromatography the β-glycosides 14a to 14c in yields of
The synthetic sequence to the glucosylated alkanolamine
precursors 8a to 8c is depicted in Scheme 3 and utilises the
glucal glycosylation procedure developed by Danishefsky.17
This method was chosen because of the high stereoselectivity
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constant (J1Ј,2Ј 8 Hz) confirmed the assignment of β-anomeric
configuration. The 13C NMR spectrum was consistent with the
proposed structure of 11a. Signals at δ 71.5 and 69.0 were
assigned to the α- and β-carbons of the Cp ring while a large
signal at δ 69.5 was attributed to the Cp carbons. The anomeric
carbon resonated at δ 103.0. Conjugates 11b and 11c showed
similar spectral data. However, a notable feature of these com-
pounds was that they were soluble in both D2O and CDCl3.
Although avoiding the use of acetyl protecting groups on the
carbohydrate was pivotal in the success of this approach it was
unclear to us whether the reductive amination process was
instrumental in the failure of the chemistry depicted in
Scheme 1. To test this, reductive aminations of the secondary
amine 8a and primary amine 15a and carbaldehyde 7 were
investigated. Treatment of a mixture of 8a and 7 with sodium
cyanotrihydroborate in acetonitrile gave the target conjugate
10a in 82% yield after column chromatography. Surprisingly
however, treatment of an equimolar mixture of primary amine
15a and 7 under similar reaction conditions gave the bis(ferro-
cenyl)amine conjugate 18 as the only ferrocene containing
product in a 38% yield. The mechanism of its formation is
unclear as the secondary amine 20, formed by the cyanotri-
hydroborate reduction of the Schiff base 19, should be the
major product on the basis of the stoichiometry of the react-
ants. Changing the ratio of 15a to 7 to 1:2 gave an increased
yield of 18 (71%).
34, 63 and 45% respectively. In each case assignment of the
β-anomeric configuration was confirmed by the magnitude of
the coupling constant (J1Ј,2Ј 7–8 Hz).19 Deblocking the amino
functionality of the phthalimides with hydrazine hydrate gave
the primary amines 15a to 15c in yields of 79, 67 and 78%
respectively. It was envisaged that methylation of the amine
functionality of compounds 15 could best be achieved by
formylation of both the amine and alcohol functionality.
Subsequent treatment with lithium aluminium hydride should
reduce the formyl ester to an alcohol and the formamide to the
desired secondary amine. Formylation of 15a to 15c proceeded
smoothly and reduction of formamide 16a gave the desired
glycosylated secondary amine 8a with the two-carbon spacer
in 77% yield. Unfortunately the reductions of formamides 16b
and 16c were relatively low yielding processes. In the latter cases
it was found that after initial formation of secondary amine
functionality an intramolecular transfer of a formyl group from
the C-2 ester group was a competing process. Subsequent
reduction gave the N,N-dimethylamines 17b and 17c as by-
products. This problem was circumvented by initial base
hydrolysis of the ester followed by lithium aluminium hydride
reduction of the formamide. Using this approach 16b was
converted into 8b in 77% yield (Scheme 3).
With the series of O-glucosylated N-methylalkanolamines in
hand the coupling reactions to the ferrocene unit were investi-
gated (Scheme 2). Reaction of 8a to 8c with methiodide salt 9
and potassium carbonate in acetonitrile gave the corresponding
conjugates 10a to 10c in yields of 78, 80 and 70% respectively.
Their formation was confirmed by spectral and microanalytical
data. The 1H and 13C NMR spectral data were consistent with
the proposed structures and showed the typical resonances
of benzylated β-glucosides and also those of substituted
ferrocenes.
The success of the above syntheses was limited by the number
of synthetic steps and the moderate yield of the Danishefsky
glycosylation process. An alternative approach would be to use
a strategy based on disconnection C. Such an approach
is shown in Scheme 4 and involves the O-glycosylation of
ferrocenylethanolamine derivative 21. It was felt that acetyl
protection of the carbohydrate could be tolerated in this system
as the tertiary amine group should not participate in acyl trans-
fer reactions.
Reaction of N-methylethanolamine with the methiodide 9
and potassium carbonate in acetonitrile at reflux gave the
ferrocene adduct 21 in 72% yield. O-Glycosylation of 21 and
penta-O-acetyl-β--glucospyranose 22, promoted by boron
trifluoride–diethyl ether (1:1),20 gave the target conjugate 23
in 34% yield after chromatographic purification. The coupling
The remaining step in the strategy towards water soluble
ferrocenylamine–carbohydrate conjugates was the hydrogen-
olytic removal of the protecting groups of the sugar unit.
Careful monitoring of the catalytic hydrogenolyses of 10a to
10c was required as reductive cleavage of the benzylic ferrocene
CH2–N bond of each substrate was a possibility. Treatment of
10a to 10c in glacial acetic acid with 10% palladium on carbon
gave the target conjugates 11a to 11c in yields of 91, 73 and 90%
respectively after purification by reversed phase column
chromatography and treatment of the residue with basic ion
exchange in methanol to ensure complete deprotonation of the
amine (Scheme 2). Compound 11a analysed for C20H29FeNO6
and this was confirmed by high resolution mass spectral data.
1
All the NMR data were assigned to the relevant H and 13C
constant (J1Ј,2Ј 8 Hz) confirmed the assignment of the
nuclei with the aid of 2-D experiments. The 1H NMR spectrum
recorded in D2O (11a was also slightly soluble in CDCl3)
showed a three proton singlet at δ 2.19 assigned to the reson-
ance of the N-methyl protons. A two proton multiplet at δ 3.54
was attributed to the α-protons of the cyclopentadienyl ring
whilst the remaining Cp protons resonated as a seven proton
multiplet at δ 3.84. The anomeric proton of the -gluco-
pyranose residue appeared as a doublet at δ 4.40. The coupling
β-anomeric configuration of the glucopyranosyl unit. All other
spectral data were consistent with the proposed structure.
Although Adam and Hall11 reported poor results for the
sodium methoxide O-deacetylation of carbohydrate–ferrocene
conjugates we felt that hydrolysis using methoxide should give
the desired result. To this end a solution of the acetylated
conjugate in methanol was treated with IRA 400 (OH) resin
using the protocol of Pathok.21 After filtration, removal of
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stated). Microanalyses were carried out by the Campbell
Microanalytical Laboratory, University of Otago. The FAB
and EI mass spectra were recorded on a Kratos MS80RFA
instrument with an Iontech ZN11NF atom gun. Optical rota-
tions were recorded on a JASCO DIP-1000 digital polarimeter.
Preparation of phthalimides 14a–14c
N-[2-(3,4,6-Tri-O-benzyl-ꢀ-D-glucopyranosyloxy)ethyl]-
phthalimide 14a. An acetone solution of dimethyldioxirane (76
ml, 6.0 mmol) was added to tri-O-benzyl--glucal (13) (1.00 g,
2.40 mmol) and 4 Å powdered molecular sieves (1.50 g) in
dichloromethane (10 ml) and the mixture stirred for 1 hour at
0 ЊC. The solvent was removed and the residue dried in vacuo
for 3 hours. THF (15 ml) was added to the residue and the
mixture cooled to Ϫ78 ЊC. A solution of 2-hydroxyethyl-
phthalimide 12a (920 mg, 4.80 mmol) in THF (10 ml) was
then added followed by the addition of an ether solution
of anhydrous zinc chloride (9 ml, 0.53 M, 4.80 mmol). The
mixture was stirred and allowed to warm slowly to room tem-
perature over 17 hours before being poured into water (150 ml)
and filtered. The filtrate was washed with dichloromethane
(2 × 100 ml) and the organic layer was dried (MgSO4) and
evaporated to dryness. The crude product mixture was purified
by silica gel column chromatography (1:19 Et2O–CH2Cl2,
RF 0.33) to give compound 14a (1.03 g, 34%) as a clear oil
which solidified on standing. Crystallisation of the solid from
dichloromethane and hexanes gave white crystals, mp 103–
105 ЊC; [α]D25 = Ϫ63.6 (c 0.4 g dlϪ1, CH2Cl2) (Found: C, 70.95; H,
6.04; N, 2.50%; MNa m/z 646, MHϩ Ϫ 2H 622. C37H37NO8
requires: C, 71.25; H, 5.98; N, 2.25%; Mϩ 623); δH(CDCl3) 3.28
(1 H, s, OH), 3.43–4.05 (9 H, m), 4.10–4.20 (1 H, m, 2-H), 4.29
(1 H, d, J 7, 1Ј-H), 4.47–4.60 (3 H, m, OCHHPh), 4.80 (1 H, d,
J 11, OCHHPh), 4.83 (1 H, d, J 6, OCHHPh), 5.02 (1 H, d,
J 11 Hz, OCHHPh), 7.11–7.41 (15 H, m, Ph) and 7.66–7.87
(4 H, m).
Scheme 4
methanol gave the target water soluble ferrocenylamine–
carbohydrate conjugate 11a in excellent yield (85%). Even
though the overall yield of 11a from N-methylethanolamine
was 23% it is superior to that obtained using the sequence
described in Schemes 2 and 3 (i.e. 10%). Furthermore the
brevity, three steps from a commercially available amine, makes
this the synthesis of choice.
As the principal aim of this work was to produce water
soluble ferrocenylamine systems the solubilities of compounds
11a–11c in water were investigated. That of 11a was measured
as 5.4 g lϪ1. The much greater solubilities of 11b and 11c, 54 and
84 g lϪ1 respective, were attributed to micelle formation. Of note
was the fact that the NMR data for 11a–11c were recorded in
D2O. Furthermore, amines 11b and 11c were also soluble in
CDCl3. The basicity of the target ferrocenylamines was also
investigated as this appears to be an important factor for their
use as ligands. Thus the pKa values of 11a and 11b were deter-
mined by standard potentiometric methods and found to be
9.2 and 9.8 respectively. These compare well with the data for
a range of ferrocenyl amines including that of FMA (8.8)
reported by Duffy et al.5
N-[3-(3,4,6-Tri-O-benzyl-ꢀ-D-glucopyranosyloxy)propyl]-
phthalimide 14b. By a similar method to that for compound 14a
using 13 (3.00 g, 7.20 mmol) and 3-hydroxypropylphthalimide
12b (3.00 g, 14.2 mmol), 14b was obtained as a white foam (2.90
g, 63%) (1:19 Et2O–CH2Cl2, RF 0.37); [α]D25 = 16.6 (c 0.4,
CH2Cl2) (Found: C, 71.77; H, 6.22; N, 2.02%; MHϩ m/z 638,
MHϩ Ϫ 2H 636. C38H39NO8 requires: C, 71.57; H, 6.16; N,
2.30%; Mϩ 637); δH(CDCl3) 1.97–2.17 (2 H, m, 2-H2), 3.39 (1 H,
s, OH), 3.44–3.83 (8 H, m), 3.94–4.04 (2 H, m, 3-H2), 4.24 (1 H,
d, J 7, 1Ј-H), 4.49–4.62 (3 H, m, OCHHPh), 4.83 (1 H, d, J 11,
OCHHPh), 4.85 (1 H, d, J 11, OCHHPh), 5.07 (1 H, d, J 11
Hz, OCHHPh), 7.15–7.45 (15 H, m, Ph) and 7.66–7.88 (4 H,
m).
Conclusion
This paper reports the successful syntheses of three water sol-
uble ferrocenylamine–carbohydrate conjugates 11a–11c. The
preferred route to 11a involved the boron trifluoride–diethyl
ether reaction of per-acetylated glucose with the substituted
ethanolamine derivative 21. Deacetylation gave the target
conjugate 11a in 23% overall yield from N-methylethanolamine.
An alternative route using the reactions of benzylated
N-glycosyloxy-N-methylamines 8a–8c with methiodide salt 9,
followed by hydrogenolytic debenzylation, also afforded the
target conjugates 11a–11c. Although the latter route is clearly
longer and less efficient, it could easily be adapted to allow the
synthesis of more complex ferrocenylamine–carbohydrate
conjugates.
N-[5-(3,4,6-Tri-O-benzyl-ꢀ-D-glucopyranosyloxy)pentyl]-
phthalimide 14c. Similarly, using compound 13 (3.00 g, 7.2
mmol) and 5-hydroxypentylphthalimide 12c (3.36 g, 14.2
mmol), 14c was obtained as a foam (2.17 g, 45%) (1:19 Et2O–
CH2Cl2, RF 0.37); [α]D25 = Ϫ10.4 (c 0.4, CH2Cl2) (Found: C, 72.21;
H, 6.81; N, 2.05%; MHϩ m/z 666, MHϩ Ϫ 2H 664. C40H43NO8
requires: C, 72.16; H, 6.51; N, 2.10%; Mϩ 665); δH(CDCl3)
1.48–1.50 (2 H, m, 3-H2), 1.60–1.79 (4 H, m, 2-H2 and 4-H2),
2.62 (1 H, d, J 2, OH), 3.44–3.78 (9 H, m), 3.93 (1 H, dt, J 10
and 6, 5-H), 4.24 (1 H, d, J 8, 1Ј-H), 4.49–4.64 (3 H, m,
OCH2Ph), 4.84 (2 H, d, J 11 Hz, OCHHPh), 4.97 (1 H, d,
J 11 Hz, OCHHPh), 7.12–7.41 (15 H, m, Ph) and 7.66–7.87
(4 H, m).
Experimental
Dichloromethane was distilled from P2O5 and tetrahydrofuran
(THF) from sodium–benzophenone under nitrogen. All other
solvents and reagents were purified using standard methods.22
The IR spectra were recorded on a Digilab FX60, NMR spectra
on a Varian VSR300 MHz spectrometer (1H and 13C as
solutions in deuteriochloroform at 300 and 75 MHz respec-
tively and referenced to residual chloroform unless otherwise
Preparation of amines 15a–15c
2-Aminoethyl 3,4,6-tri-O-benzyl-ꢀ-D-glucopyranoside 15a.
Hydrazine monohydrate (1 ml) was added to compound 14a
(130 mg, 0.21 mmol) in methanol (30 ml) and the solution
stirred at room temperature overnight. The solvent was removed
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by rotary evaporation until a syrup remained. Dilution with
ethanol and removal of the solvent by rotary evaporation was
repeated several times to remove residual hydrazine until a
white solid remained. The product was extracted into chloro-
form (100 ml), the solvent removed and the solid residue
crystallised from dichloromethane and hexanes to give white
crystals of 15a (81 mg, 79%), mp 79–81 ЊC, [α]D25 = 2.7 (c 0.4,
CH2Cl2) (Found: MHϩ m/z 494.2538. C29H35NO6 requires
494.2543); δH(CDCl3) 2.87–2.95 (2 H, m, 2-H2), 3.46–3.77 (7 H,
m), 3.91–4.00 (1 H, m, 1-H), 4.30 (1 H, d, J 7, 1Ј-H), 4.50–4.64
(3 H, m, OCH2Ph), 4.84 (2 H, d, J 11, OCH2Ph), 5.00 (1 H, d,
J 11 Hz, OCHHPh) and 7.12–7.43 (15 H, m, Ph).
5-Formamidopentyl 3,4,6-tri-O-benzyl-2-O-formyl-ꢀ-D-gluco-
pyranoside 16c. Compound 15c (1.20 g, 2.2 mmol) as for 16b
gave 16c as a white foam (0.80 g, 60%) after purification
by silica gel column chromatography (1:4 Et2O–CH2Cl2);
[α]D25 = Ϫ8.8 (c 0.4, CH2Cl2) (Found: C, 69.08; H, 7.09; N, 2.43%;
MHϩ m/z 592. C34H41NO8 requires: C, 69.01; H, 6.98; N, 2.34%;
MHϩ m/z 592); δH(CDCl3) 1.31–1.43 (2 H, m), 1.46–1.64 (4 H,
m), 3.27 (2 H, apparent q, J 4, 5-H2), 3.42–3.52 (2 H, m, 1-H
and 6Ј-H), 3.65–3.78 (4 H, m), 3.89 (1 H, dt, J 10 and 6, 1-H),
4.37 (1 H, d, J 8, 1Ј-H), 4.54 (1 H, d, J 12, OCHHPh), 4.56 (1
H, d, J 11, OCHHPh), 4.62 (1 H, d, J 12, OCHHPh), 4.69 (1 H,
d, J 11, OCHHPh), 4.71 (1 H, t, J 10, 2-H), 4.81 (1 H, d, J 11,
OCHHPh), 4.82 (1 H, d, J 11, OCHHPh), 5.93 (1 H, s,
NHCHO), 7.18–7.40 (15 H, m, Ph), 8.03 (1 H, d, J 1) and 8.13
(1 H, d, J 2 Hz).
3-Aminopropyl 3,4,6-tri-O-benzyl-ꢀ-D-glucopyranoside 15b.
From compound 14b (1.60 g, 3.2 mmol) by a similar method to
that for 15a; as white crystals (1.07 g, 67%); mp 95 ЊC;
[α]D25 = Ϫ7.4 (c 0.4, CH2Cl2) (Found: C, 70.64; H, 7.53; N, 3.08%;
MHϩ m/z 508, MHϩ Ϫ H2O 490. C32H41NO6 requires: C, 70.98;
H, 7.35; N, 2.76%; MHϩ m/z 508); δH(CDCl3) 1.66–1.87 (2 H,
m, 2-H2), 2.79–3.00 (2 H, m, 3-H2), 3.46–3.78 (7 H, m), 4.04–
4.13 (1 H, m, 1-H), 4.29 (1 H, d, J 7, 1Ј-H), 4.49–4.63 (3 H, m,
OCH2Ph), 4.83 (1 H, d, J 11, OCHHPh), 4.84 (1 H, d, J 11,
OCHHPh), 5.00 (1 H, d, J 11 Hz, OCHHPh) and 7.12–7.43 (15
H, m, Ph).
Preparation of methylamines 8a–8c
2-(N-Methylamino)ethyl 3,4,6-tri-O-benzyl-ꢀ-D-glucopyrano-
side 8a. Compound 16a (1.5 g, 2.7 mmol) was dissolved in dry
THF (200 ml), lithium aluminium hydride (800 mg) added care-
fully then the mixture was heated at reflux for 3 hours. Excess of
lithium aluminium hydride was quenched by adding water
dropwise. The mixture was then poured into dichloromethane
(200 ml) and water (200 ml), filtered and the residue washed
with dichloromethane (200 ml) and water (200 ml). The
organic layer was separated, washed with water (300 ml), dried
(MgSO4) and evaporated to dryness. The crude product was
purified by silica gel column chromatography (1:1 MeOH–
ethylacetate; RF = 0.12) to give 8a (1.06 g, 77%) as a white foam;
[α]D25 = Ϫ0.5 (c 0.4, CH2Cl2) (Found: C, 70.61; H, 7.52; N, 2.55%;
MHϩ m/z 508. C30H37NO6 requires: C, 70.98; H, 7.35; N, 2.76%;
MHϩ m/z 508); δH(CDCl3) 2.45 (3 H, s, CH3), 2.82 (2 H, t, J 5,
2-H2), 3.46–3.77 (7 H, m), 4.04 (1 H, dt, J 11 and 5, 1-H), 4.29
(1 H, d, J 7, 1Ј-H), 4.52 (1 H, d, J 11, OCHHPh), 4.53 (1 H, d,
J 12, OCHHPh), 4.60 (1 H, d, J 12, OCHHPh), 4.83 (1 H, d,
J 11, OCHHPh), 4.84 (1 H, d, J 11, OCHHPh) and 5.00 (1 H,
d, J 11 Hz, OCHHPH).
5-Aminopentyl 3,4,6-tri-O-benzyl-ꢀ-D-glucopyranoside 15c.
From compound 14c (1.67 g, 2.5 mmol) as a clear syrup (1.30 g,
78%). [α]D25 Ϫ1.2 (c 0.4, CH2Cl2) (Found: MHϩ m/z 536.3029.
C32H41NO6 requires: 536.3012); δH(CDCl3) 1.37–1.55 (4 H, m),
1.60–1.73 (2 H, m), 2.71 (2 H, t, J 7, 5-H2), 3.47–3.80 (7 H, m),
3.98 (1 H, dt, J 10 and 6, 1-H), 4.27 (1 H, d, J 7, 1Ј-H), 4.53–
4.66 (3 H, m, CHHPh), 4.86 (2 H, d, J 11, OCHHPh), 5.00
(1 H, d, J 11 Hz, OCHHPh) and 7.17–7.44 (15 H, m, Ph).
Preparation of formamides 16a–16c
2-Formamidoethyl 3,4,6-tri-O-benzyl-2-O-formyl-ꢀ-D-gluco-
pyranoside 16a. Pyridine (5 ml) was added slowly to a stirred
solution of compound 15a (200 mg, 0.41 mmol) in formic acetic
anhydride (6 ml). A cold water bath was used to control the
temperature of the initial reaction and the mixture stirred at
room temperature overnight. The solvent was removed and the
crude product dissolved in dichloromethane (60 ml) and
washed with water (2 × 100 ml). The organic layer was dried
(MgSO4), evaporated to dryness and the residue crystallised
from dichloromethane and hexanes to give white crystals of 16a
(156 mg, 70%), mp 78–80 ЊC, [α]D25 = Ϫ12.63 (c 0.4, CH2Cl2)
(Found: C, 67.71; H, 6.32; N, 2.56%; MHϩ m/z 550,
MHϩ Ϫ CO 522. C31H35NO8 requires: C, 67.74; H, 6.42; N,
2.55%; MHϩ m/z 550); δH(CDCl3) 3.22–3.33 (1 H, m, 2-H),
3.49–3.74 (7 H, m), 3.81–3.89 (1 H, m, 1-H), 4.35 (1 H, d, J 8,
1Ј-H), 4.53 (2 H, s, OCH2Ph), 4.54 (1 H, d, J 11, OCHHPh),
4.68 (1 H, d, J 11, OCHHPh), 4.81 (2 H, d, J 11 Hz,
2 × OCHHPh), 6.61 br (1 H, s), 7.15–7.38 (15 H, m, Ph), 7.90
(1 H, s, CHO) and 7.99 (1 H, s),
3-(N-Methylamino)propyl 3,4,6-tri-O-benzyl-ꢀ-D-glucopyr-
anoside 8b. From compound 16b (3.20 g, 6.1 mmol) by the
same method as for 8a but two products were found 8b and 17b.
Crystallisation and recrystallisation from dichloromethane and
hexanes gave 8b (1.35 g, 46%) as fine long white needles, mp
93 ЊC; [α]D25 = Ϫ6.7 (c 0.52, CH2Cl2) (Found: C, 71.31; H, 7.83; N,
2.69%; MHϩ m/z 522. C31H39NO6 requires: C, 71.37; H, 7.54; N,
2.69%; MHϩ m/z 522); δH(CDCl3) 1.76–1.86 (2 H, m, 2-H2),
2.41 (3 H, s, CH3), 2.66–2.84 (2 H, m, 3-H2), 3.46–3.79 (7 H, m),
4.06–4.13 (1 H, m, 1-H), 4.27 (1 H, d, J 7, 1Ј-H), 4.51 (1 H, d,
J 11, OCHHPh), 4.53 (1 H, d, J 12, OCHHPh), 4.61 (1 H,
d, J 12, OCHHPh), 4.82 (1 H, d, J 11, OCHHPh), 4.84 (1 H, d,
J 11, OCHHPh) and 5.03 (1 H, d, J Hz, OCHHPh). Removal
of solvent from the mother liquors gave 3-(N,N-dimethyl-
amino)propyl 3,4,6-tri-O-benzyl-β--glucopyranoside 17b
(0.63 g, 21%) as a colourless oil. [α]D25 = 3.75 (c 0.44, CH2Cl2)
(Found: C, 71.91; H, 7.99; N, 2.61%; MHϩ m/z 537. C32H41NO6
requires: C, 71.75; H, 7.72; N, 2.62%; MHϩ m/z 537);
δH(CDCl3) 1.64–1.77 (1 H, m, 2-H), 1.80–1.94 (1 H, m, 2-H),
2.23 (6 H, s, N(CH3)2), 2.41–2.47 (2 H, m, 3-H2), 3.46–3.78 (7 H,
m), 4.07–4.14 (1 H, m, 1-H), 4.26 (1 H, d, J 7, 1Ј-H), 4.50 (1 H,
d, J 11, OCHHPh), 4.53 (1 H, d, J 12, OCHHPh), 4.60 (1 H, d,
J 12, OCHHPh), 4.81 (1 H, d, J 11, OCHHPh), 4.84 (1 H, d,
J 11, OCHHPh) and 5.03 (1 H, d, J 11 Hz, OCHHPh).
3-Formamidopropyl 3,4,6-tri-O-benzyl-2-O-formyl-ꢀ-D-gluco-
pyranoside 16b. From compound 15b (550 mg, 1.1 mmol) by a
similar method except that the crude product was purified by
silica gel column chromatography (1:1 Et2O–CH2Cl2,
RF = 0.24) to give 16b (519 mg, 85%) as a foam; [α]D25 = Ϫ27.4 (c
0.4, CH2Cl2) (Found: C, 67.93; H, 6.52; N, 2.64%; MHϩ m/z
564. C32H37NO8 requires: C, 68.19; H, 6.62; N, 2,49%; MHϩ m/z
564); δH(CDCl3) 1.71–1.82 (2 H, m, 2-H2), 3.25–3.37 (1 H, m,
3-H), 3.38–3.46 (1 H, m, 3-H), 3.47–3.77 (6 H, m), 3.84–3.93
(1 H, m, 1-H), 4.39 (1 H, d, J 8, 1Ј-H), 4.52 (1 H, d, J 17,
OCHHPh), 4.54 (1 H, d, J 11, OCHHPh), 4.58 (1 H, d, J 17,
OCHHPh), 4.69 (1 H, d, J 11, OCHHPh), 4.81 (1 H, d, J 11,
OCHHPh), 4.82 (1 H, d, J 11, OCHHPh), 4.91 (1 H, t, J 8, 2Ј-
H), 6.36–6.44 (1 H, NHCHO), 7.12–7.40 (15 H, m, Ph), 7.91
(1 H, d, J 2) and 8.00 (1 H, d, J 1 Hz).
5-(N-Methylamino)pentyl
3,4,6-tri-O-benzyl-ꢀ-D-glucopyr-
anoside 8c. From compound 16c (1.75 g, 3.0 mmol) by the
method for 8a except that the crude product was crystallised
from dichloromethane and hexanes to give 8c (0.90 g, 56%) as
fine long white needles; mp 96 ЊC; [α]D25 = Ϫ6.5 (c 0.42, CH2Cl2)
(Found: C, 72.21; H, 8.06; N, 2.53%; MHϩ m/z 550. C33H43NO6
J. Chem. Soc., Dalton Trans., 2000, 1403–1409
1407

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requires: C, 72.10; H, 7.89; N, 2.55%; MHϩ m/z 550);
δH(CDCl3) 1.40–1.51 (2 H, m, 3-H2), 1.51–1.62 (2 H, m, 4-H2),
1.62–1.74 (2 H, m, 2-H2), 2.43 (3 H, s, CH3), 2.46–2.65 (2 H, m,
5-H2), 3.46–3.62 (5 H, m), 3.68 (1 H, dd, J 11 and 5, 6Ј-H), 3.73
(1 H, dd, J 11 and 2, 6Ј-H), 4.00 (1 H, dt, J 10 and 6, 1-H), 4.25
(1 H, d, J 7, 1Ј-H), 4.53 (1 H, d, J 11, OCHHPh), 4.55 (1 H, d,
J 12, OCHHPh), 4.62 (1 H, d, J 12, OCHHPh), 4.83 (1 H, d,
J 11, OCHHPh), 4.84 (1 H, d, J 11, OCHHPh) and 4.99 (1 H,
d, J 11 Hz, OCHHPh).
3.41–3.61 (5 H, m), 4.02–4.11 (8 H, m, Cp), 4.14–4.16 (1 H, m,
Cp), 4.17–4.20 (1 H, m, Cp), 4.23 (1 H, d, J 8, 1Ј-H), 4.52 (1 H,
d, J 11, OCHHPh), 4.54 (1 H, d, H 12, OCHHPh), 4.62 (1 H, d,
J 12, OCHHPh), 4.81 (1 H, d, J 11, OCHHPh), 4.85 (1 H, d,
J 11, OCHHPh) and 5.00 (1 H, d, J 11 Hz, OCHHPh).
Preparation of water soluble ferrocenes 11a–11c
N-[2-(ꢀ-D-Glucopyranosyloxy)ethyl]-N-methylaminomethyl-
ferrocene 11a. Compound 10a (100 mg, 0.14 mmol) was
dissolved in distilled concentrated acetic acid (25 ml), 10%
palladium on carbon (35 mg) added and the mixture stirred
under an atmosphere of hydrogen for 24 hours. The Pd/C was
removed by filtration through Celite, and a further portion of
10% Pd/C (35 mg) added. The mixture was stirred under an
atmosphere of hydrogen for 24 hours. The solids were removed
by filtration and the solution was evaporated to dryness. The
residue was subjected to reversed-phase C-18 silica gel column
chromatography (3:7 water–MeOH), the solvent removed and
the crude product dissolved in Me(OH) (25 ml) and stirred in
the presence of IRA 400 (OH) resin (200 mg) to ensure that the
amino group had not been protonated. The mixture was filtered
and evaporated to dryness to give 11a (52 mg, 91%) as a yellow
foam; [α]D25 = Ϫ8.0 (c 0.4, CH2Cl2) (Found: C, 54.53; H, 6.59; N,
3.02%; Mϩ m/z 435.1349. C20H29FeNO6 requires: C, 55.18; H,
6.72; N, 3.22%; Mϩ m/z 435.1344); δH(D2O) 2.19 (3 H, s, CH3),
2.54–2.73 (2 H, m, 1-H2), 3.23–3.51 (4 H, m), 3.54 (2 H, s,
CH2Fc), 3.67–3.76 (2 H, m, 2-H and 6Ј-H), 3.90 (1 H, dd, J 12
and 2, 6Ј-H), 3.94–4.23 (1 H, m, 2-H), 4.21–4.26 (7 H, m, Cp),
4.30–4.34 (2 H, m, Cp) and 4.40 (1 H, d, J 8 Hz, 1Ј-H).
An alternative preparation of compound 8b. IRA 400 (OH)
resin (2 g) was added to a stirred solution of compound 16b
(0.90 g, 1.7 mmol) in MeOH (150 ml). After 1 hour the solution
was filtered and evaporated to dryness. Lithium aluminium
hydride (400 mg) was added carefully to the residue dissolved in
THF (45 ml) and the mixture heated at reflux for 2 hours. Water
was added dropwise until the remaining lithium aluminium
hydride had been quenched and the mixture poured into
dichloromethane (150 ml) and water (150 ml). After filtration
the residue was washed with dichloromethane (200 ml) and
water (200 ml), the organic layer separated, washed with water
(200 ml), dried (MgSO4) and evaporated to dryness. Crystallis-
ation from dichloromethane and hexanes gave 16b (0.64 g, 77%)
as fine long white needles identical to that described above.
Preparation of ferrocenes 10a–10c
N-Methyl-N-[2-(3,4,6-tri-O-benzyl-ꢀ-D-glucopyranosyloxy)-
ethyl]aminomethylferrocene 10a. Anhydrous K2CO3 (470 mg,
3.4 mmol) and the methiodide salt 9 (440 mg, 1.1 mmol) were
added to compound 8a (190 mg, 0.37 mmol) in CH3CN (90 ml)
and the mixture was refluxed overnight. After filtering off the
K2CO3 the CH3CN was removed by rotary evaporation. The
residue was dissolved in dichloromethane (200 ml), washed
with water (2 × 300 ml), dried (MgSO4) and evaporated to
dryness. The crude product was purified by silica gel column
chromatography (1:39 MeOH–CH2Cl2, RF 0.33) to give 10a
(347 mg, 78%) as a yellow foam; [α]D25 = Ϫ18.9 (c 0.3, CH2Cl2)
(Found: C, 69.94; H, 6.61; N, 1.71%; Mϩ m/z 705. C41H47FeNO6
requires: C, 69.78; H, 6.71; N, 1.99%; Mϩ 705); δH(CDCl3) 2.23
(3 H, s, CH3), 2.50–2.68 (2 H, m, 1-H2), 3.45–3.77 (9 H, m),
3.98–4.07 (1 H, m, 2-H), 4.1–4.22 (9 H, m, Cp), 4.26 (1 H, d,
J 8, 1Ј-H), 4.50 (1 H, d, J 11, OCHHPh), 4.53 (1 H, d, J 12,
OCHHPh), 4.59 (1 H, d, J 12, OCHHPh), 4.81 (1 H, d, J 11,
OCHHPh), 4.85 (1 H, d, J 11, OCHHPh) and 5.01 (1 H, d, J 11
Hz, OCHHPh).
N-[3-(ꢀ-D-Glucopyranosyloxy)propyl]-N-methylaminomethyl-
ferrocene 11b. From compound 10b (200 mg, 0.28 mmol) as for
10a, except column chromatography was carried out on silica
gel using 2:9 MeOH–CH2Cl2 (RF = 0.10) as eluent, as a yellow
foam (91 mg, 73%); [α]D25 = Ϫ10.9 (c 0.5, CH2Cl2) (Found: C,
55.52; H, 7.63; N, 2.81%; Mϩ m/z 449, MHϩ 450. C21H31FeNO6
requires: C, 56.13; H, 6.95; N, 3.12%; Mϩ m/z 449); δH(D2O)
1.73–1.86 (2 H, m, 2-H2), 2.13 (3 H, s, CH3), 2.36–2.46 (2 H, m,
1-H2), 3.26 (1 H, t, J 9, 2Ј-H), 3.34–3.52 (5 H, m, 3Ј-, 4Ј-, 5Ј-H
and CH2Fc), 3.56–3.77 (2 H, m, 3-H and 6Ј-H), 3.84–3.94 (2 H,
m, 3-H and 6Ј-H), 4.22 br (7 H, s, Cp), 4.27s (2 H, s, Cp) and
4.38 (1 H, d, J 8 Hz, 1Ј-H).
N-[5-(ꢀ-D-Glucopyranosyloxy)pentyl]-N-methylaminomethyl-
ferrocene 11c. From compound 10c (278 mg, 0.37 mmol),
except column chromatography was carried out on silica gel
with 2:9 MeOH–CH2Cl2 (RF = 0.12) as the eluent, as a yellow
foam (160 mg, 90%); [α]D25 = Ϫ22.0 (c 0.5, CH2Cl2) (Found: C,
57.26; H, 6.87; N, 2.71%; Mϩ m/z 477, MNaϩ 500.
C23H35FeNO6 requires: C, 57.86; H, 7.39; N, 2.93%; Mϩ 477);
δH(D2O) 1.24–1.39 (2 H, m, 3-H2), 1.41–1.55 (2 H, m, 2-H2),
1.56–1.69 (2 H, m, 4-H2), 1.97 (3 H, s, CH3), 2.23–2.35 (2 H,
m, 1-H2), 3.26 (1 H, t, J 8, 2Ј-H), 3.35–3.52 (5 H, m), 3.55–3.66
(1 H, m, 5-H), 3.69–3.78 (1 H, m, 6Ј-H), 3.84–3.94 (2 H, m, 5-H
and 6Ј-H), 4.14–4.26 (9 H, m, Cp) and 4.38 (1 H, d, J 8 Hz,
1Ј-H).
N-Methyl-N-[3-(3,4,6-tri-O-benzyl-ꢀ-D-glucopyranosyloxy)-
propyl]aminomethylferrocene 10b. From compound 8b (200 mg,
0.38 mmol) as for 10a, except for column chromatography the
eluent was 1:19 MeOH–CH2Cl2 (RF = 0.15), as a yellow foam
(220 mg, 80%); [α]D25 = Ϫ1.3 (c 0.4, CH2Cl2) (Found: C, 69.75; H,
6.92; N, 1.82%; MHϩ m/z 720. C42H49FeNO6 requires: C, 70.09;
H, 6.86; N, 1.95%; MHϩ m/z 720); δH(CDCl3) 1.68–1.80 (1 H,
m, 2-H), 1.81–1.95 (1 H, m, 2-H), 2.18 (3 H, s, CH3), 2.41–2.58
(2 H, m, 1-H2), 3.45–3.77 (9 H, m), 4.03–4.10 (1 H, m, 3-H),
4.10–4.15 (7 H, m, Cp), 4.20–4.24 (2 H, m, Cp), 4.28 (1 H, d,
J 8, 1Ј-H), 4.52 (1 H, d, J 11, OCHHPh), 4.53 (1 H, d, J 12,
OCHHPh), 4.61 (1 H, d, J 12, OCHHPh), 4.83 (1 H, d, J 11,
OCHHPh), 4.86 (1 H, d, J 11, OCHHPh) and 5.06 (1 H, d, J 11
Hz, OCHHPh).
Preparation of compound 10a via reductive amination of
ferrocenecarbaldehyde 7
A mixture of ferrocenecarbaldehyde 7 (51 mg, 0.13 mmol),
glycoside 8a (45 mg, 0.09 mmol), and sodium cyanotrihydrobo-
rate (40 mg, 0.63 mmol) in acetonitrile (10 ml) was stirred for 18
hours. Dichloromethane (50 ml) was added and the organic
layer washed with a saturated aqueous solution of sodium
hydrogencarbonate (50 ml) and water (50 ml). The organic layer
was then dried (MgSO4) and evaporated to dryness. The residue
was purified by silica gel column chromatography (1:39
MeOH–CH2Cl2, RF = 0.33) to give compound 10a (51 mg,
82%) as a yellow foam identical to that reported above.
N-Methyl-N-[5-(3,4,6-tri-O-benzyl-ꢀ-D-glucopyranosyloxy)-
pentyl]aminomethylferrocene 10c. From compound 8c (500 mg,
0.91 mmol) using 1:19 MeOH–CH2Cl2 (RF = 0.18) as the
eluent, as a yellow foam (480 mg, 70%); [α]D25 = Ϫ14.1 (c 0.4,
CH2Cl2) (Found: C, 70.41; H, 7.43; N, 1.87%; MHϩ m/z 748.
C44H53FeNO6 requires: C, 70.67; H, 7.14; N, 1.87%; MHϩ m/z
748); δH(CDCl3) 1.35–1.49 (2 H, m, 3-H2), 1.53–1.77 (4 H, m,
2-H2 and 4-H2), 2.09 (3 H, s, N-CH3), 2.13 (1 H, dt, J 12
and 8, 4-H), 2.51 (1 H, dt, J 12 and 8, 4-H), 3.39 (2 H, s, CH2Fc),
1408
J. Chem. Soc., Dalton Trans., 2000, 1403–1409

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Preparation of bis(ferrocene) 18
ml) and stirred with OHϪ IRA 400 resin (800 mg) for 3 hours.
The reaction mixture was filtered and evaporated to dryness to
give the target product 11a (43 mg, 85%) as a yellow foam. The
spectral and physical data were identical to those of a sample
prepared above.
A mixture of ferrocenecarbaldehyde 7 (650 mg, 1.67 mmol),
glycoside 15a (330 mg, 0.67 mmol), and sodium cyanotri-
hydroborate (295 mg, 4.7 mmol) in CH3CN (25 ml) was stirred
for 18 hours at room temperature. Dichloromethane (100 ml)
was then added and the organic layer washed with a saturated
aqueous solution of sodium hydrogencarbonate (150 ml) and
water (150 ml). The organic layer was then dried (MgSO4)
and evaporated to dryness. The residue was purified by silica
gel column chromatography (1:39 MeOH–CH2Cl2) to give
compound 18 (155 mg, 27%) as a yellow foam (Found: C, 68.84;
H, 6.51; N, 1.76%; MHϩ m/z 890, MHϩ Ϫ CH2 Ϫ Fc 758.
C51H55FeNO6 requires C, 68.85; H, 6.23; N, 1.57%; MHϩ m/z
890); δH(CDCl3) 1.27 (3 H, s, CH3), 2.45–2.65 (2 H, m, 1-H2),
3.41–3.79 (10 H, m), 3.90–4.01 (1 H, m, 2-H), 4.09–4.30 (20 H,
m, Cp and 6Ј-H2), 4.51 (1 H, d, J 11, OCHHPh), 4.53 (1 H, d,
J 12, OCHHPh), 4.60 (1 H, d, J 12, OCHHPh), 4.83 (1 H, d,
J, OCHHPh), 4.88 (1 H, d, J 7, OCHHPh), 5.11 (1 H, d, J 11
Hz, OCHHPh) and 7.14–7.48 (15 H, m, Ph).
Acknowledgements
The authors wish to thank the University of Otago for financial
support. We also thank Mrs M. Dick and Mr R. M. McAllister
for microanalyses, Mr B. Clark (University of Canterbury) for
the measurement of mass spectra, and Dr M. Thomas and Mr
W. Redmond for assistance in acquiring NMR spectra.
References
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Preparation of N-(2-hydroxyethyl)-N-methylaminomethyl-
ferrocene 21
N-Methylethanolamine (820 mg, 11 mmol) was dissolved in dry
acetonitrile (100 ml). Anhydrous potassium carbonate (2 g, 14
mmol) and methiodide salt 9 (5 g, 13 mmol) were added and the
mixture was heated under reflux overnight. After filtering the
solvent was removed by rotary evaporation. The remaining
crude product was dissolved in dichloromethane (200 ml),
washed with water (2 × 300 ml), dried (MgSO4) and evaporated
to dryness. The crude product mixture was purified by silica
gel column chromatography (1:39 MeOH–CH2Cl2) to give
compound 21 (2.55 g, 72%) as a yellow solid, mp 96–97 ЊC
(Found: Mϩ m/z 273.0817; C14H19FeNO requires 273.0816);
δH(CDCl3) 2.19 (3 H, s, CH3), 2.52 (2 H, t, J 5, 1-H2), 3.37 br
(1 H, s, OH), 3.48 (2 H, s, FcCH2), 3.57 (2 H, t, J 5 Hz, 2-H2),
4.11 (5 H, s, Cp), 4.12–4.13 (2 H, m, Cp) and 4.15–4.16 (2 H, m,
Cp).
10 L. Bao-Guo, A. Juan, B. Zhan-Xi and Z. Hai-Ying, Gaodeng
Xuexiao Huaxue Xuebao, 1996, 17, 1725; L. L. Troitskaya and V. I.
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13 M. Wenzel, M. Schieder and J. Macha, Int. J. Appl. Radiat. Isot.,
1981, 32, 797; M. Schneider and M. Wenzel, J. Labelled Compd.
Radiopharm., 1981, 18, 293.
14 G. Grynkieewicz and J. N. BeMiller, Carbohydr. Res., 1984, 131, 273.
15 J. L. Kerr, J. S. Landells, D. S. Larsen, B. H. Robinson and
J. Simpson, J. Chem. Soc., Dalton Trans., 2000, DOI: 10.1039/
a908513k.
16 M. A. Bernstein and L. D. Hall, Carbohydr. Res., 1980, 78, c1–c3.
17 R. L. Halcomb and S. J. Danishefsky, J. Am. Chem. Soc., 1989, 111,
6661.
18 V. M. Ostrovaskaya, I. A. Shunskaya and L. V. Lomakina, Metody
Poluch. Khim. Prep., 1974, 26, 237.
19 R. M. Silverstein, G. Clayton Bassler and T. C. Morrill,
Spectroscopic Identification of Organic Compounds, 5th edn., John
Wiley and Sons, New York, 1991.
Preparation of ferrocenylamine-glucose conjugate 23
Penta-O-acetyl--glucopyranose 22 (500 mg, 1.28 mmol) and
compound 21 (1.00 g, 3.60 mmol) were dissolved in dry CH2Cl2
(10 ml) in a 50 ml round bottom flask. Boron trifluoride–diethyl
ether (5 ml) was added and the mixture stirred under a CaCl2
drying tube for 18 hours. The mixture was poured into water
(200 ml) and extracted into CH2Cl2 (150 ml). The organic layer
was washed with a saturated aqueous solution of sodium
hydrogencarbonate (150 ml) and then water (150 ml). The
organic layer was dried (MgSO4) and evaporated to dryness.
The crude product mixture was purified by silica gel column
chromatography (1:39 MeOH–CH2Cl2) to give 23 (264 mg,
34%) as a yellow solid, mp 117–119 ЊC (Found: C, 55.02; H,
5.96; N, 2.31%; MHϩ m/z 603. C28H37FeNO10 requires C, 55.73;
H, 6.18; N, 2.32%; MHϩ m/z 603); δH(CDCl3) 2.00 (3 H, s,
OAc), 2.02 (3 H, s, OAc), 2.04 (3 H, s, OAc), 2.08 (3 H, s, OAc),
2.33 (3 H, s, NCH3), 2.72 (2 H, t, J 6, 1-H2), 3.63 (2 H, s,
CH2Fc), 3.67–3.76 (2 H, m, 2-H and 5Ј-H), 3.92–4.01 (1 H, m,
2-H), 4.14 (5 H, s, Cp), 4.15–4.29 (6 H, m, Cp and 6Ј-H2), 4.55
(1 H, d, J 8 Hz, 1Ј-H), 4.94–5.23 (3 H, m, 2Ј-H, 3Ј-H and 4Ј-H).
20 T. Takano, F. Nakatsubo and K. Murakami, Carbohydr. Res., 1990,
203, 341.
21 V. P. Pathok, Synth. Commun., 1993, 23, 83.
22 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, 2nd edn., Pergamon Press, Oxford, 1980.
Preparation of compound 11a
Peracetate 22 (70 mg, 0.12 mmol) was dissolved in MeOH (20
J. Chem. Soc., Dalton Trans., 2000, 1403–1409
1409