Iridium-catalysed condensation of alcohols and amines as a method for aminosugar synthesis

Article abstract of DOI:10.1039/c1cc12800k

Primary carbohydrate amines at primary and secondary carbons are alkylated by alcohols in the presence of [Cp*IrCl₂]₂. When primary carbohydrate alcohols are used as the coupling partners and in the presence of Cs₂CO₃

Full text of DOI:10.1039/c1cc12800k

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COMMUNICATION
Iridium-catalysed condensation of alcohols and amines as a method for
aminosugar synthesisw
a
a
a
Ian Cumpstey,*ab Santosh Agrawal, K. Eszter Borbas and Belen Martın-Matute*
´
´
Received 12th May 2011, Accepted 26th May 2011
DOI: 10.1039/c1cc12800k
Primary carbohydrate amines at primary and secondary carbons
are alkylated by alcohols in the presence of [Cp*IrCl2]2. When
primary carbohydrate alcohols are used as the coupling partners
and in the presence of Cs2CO3, amine-linked pseudodisaccharides
are obtained. Secondary carbohydrate alcohols are unaffected
Scheme 1 Alkylation of C6 amine a-Man-1 with cyclohexanol (2a).
under these conditions, which allows regioselective reactions.
the hydroxyl groups protected (a-Man-1) was used as a test
system with cyclohexanol 2a (5 equiv.) as the alkylating
reagent (Scheme 1). We found that with a catalyst loading of
1 mol% of [Cp*IrCl2]2, at 120 1C in toluene, the secondary
amine a-Man-3 was formed in excellent yield (see ESIw for
optimisation of the reaction conditions). The addition of
NaHCO3 (25 mol%) did not affect the efficacy of this reaction,
which contrasts with earlier results on different substrates
(anilines rather than carbohydrate amines).8b
In this communication, we address the use of carbohydrates as
cheap, renewable and densely functionalised potential building
blocks1 for transition metal-catalysed organic synthesis. In
particular, we focus on CꢀN bond formation in the synthesis
of structurally varied aminosugars, either by alkylation of
carbohydrate primary amines, or by amination of carbohydrate
alcohols. Classical methods for amine bond formation, such as
alkylation with halides or pseudohalides,2 oxidation and
reductive amination,3 or Mitsunobu4 chemistry with sulfonamides,
result in the production of stoichiometric by-products and
In a somewhat more challenging system, hexopyranosides
with a primary amine at C3 and with a secondary alcohol
unprotected (viz b-Glc-4, b-Man-5 and a-Man-6)y were tested
as substrates (Scheme 2). Here again the alkylation reaction
with cyclohexanol (2a) proceeded efficiently to give the secondary
amine products for all of the different configurations tested.
Products due to redox epimerisation16,17 or amination of the
unprotected secondary alcohol groups were not detected.
Benzyl alcohol (2b) could also be used as an alkylating
reagent, affording b-Glc-7b in excellent yield.
involve multistep sequences.
A catalytic redox-activated
condensation reaction between alcohols and amines to give
higher order amines and water is an attractive alternative.5,6
This process was described in the early 1980s,5,7 and has
recently gained popularity with the development of efficient
homogeneous catalysts based on ruthenium, rhodium and
iridium.8–14 To date, the substrate scope has been limited to
rather simple molecules. The reactivity of carbohydrate alcohols in
the catalytic amination reaction does not appear to be known,
while the catalytic alkylation of carbohydrate amines with
simple alcohols (as solvents) over heterogeneous catalysts has
been reported,15 but not studied in detail. Focussing on the
[Cp*IrCl2]2 complexz as introduced by Fujita et al.,8 we have
examined the scope of the reaction with respect to functional-
isation of carbohydrate amines with alcohols; and also the
functionalisation of carbohydrate alcohols with amines,
including regioselectivity aspects.
First, we considered the reactivity of carbohydrate amines
towards non-carbohydrate alcohols. A primary C6 amine with
a Department of Organic Chemistry, The Arrhenius Laboratory,
Stockholm University, 106 91 Stockholm, Sweden.
E-mail: belen@organ.su.se, ian.cumpstey@sjc.oxon.org;
Fax: +46 (0)8 15 162477; Tel: +46 (0)8 154908
b ICSN-CNRS, 91198 Gif-sur-Yvette CEDEX, France
w Electronic supplementary information (ESI) available: Optimisation
of reaction conditions, experimental details and spectra of new
compounds. See DOI: 10.1039/c1cc12800k
Scheme 2 Alkylation of C3 carbohydrate amines with alcohols.
Chem. Commun., 2011, 47, 7827–7829 7827
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NaHCO3 than with Cs2CO3.8b In a control experiment without
added alcohol, the carbohydrate amine a-Glc-12 failed to give a
pseudodisaccharide product, indicating that the C2 symmetric
diglucose Glc,Glc-14 does arise from a redox condensation
involving the carbohydrate alcohol a-Glc-13. A dimannose
(Man,Man-16) was similarly formed by reaction of amine
a-Man-1 with C6 alcohol a-Man-15, and an unsymmetrical
Glc,Man-17 pseudodisaccharide was formed either by
condensation of amine a-Man-1 with alcohol a-Glc-13, or by
reaction of amine a-Glc-12 with alcohol a-Man-15 (Scheme 4).
In these three reactions, the yields were lower, the remainder
being unreacted starting materials and unidentified non-polar
by-products.
Scheme 3 Alkylation of amine a-Man-10 with alcohols 2a, 2c–d.
We went on to investigate the alkylation of an essentially
unprotected aminosugar a-Man-10. Earlier reactions had been
carried out in toluene, but this solvent was unsuitable here as
the substrate a-Man-10 was insoluble. Using the alcohol itself
as solvent was found to work well. With secondary alcohols 2a
and 2c, the products were the secondary amines, while a
primary alcohol (2d) gave the tertiary amine as the only
product as a result of two consecutive alkylations (Scheme 3).
The use of carbohydrate alcohols as latent electrophiles is a
challenging goal. The alcohol carbons of carbohydrates are
electron-poor, which makes them resistant to oxidation
by a transition-metal-catalysed hydrogen-transfer mechanism.
To the best of our knowledge, there are no reports on the
redox-activated amination reaction of carbohydrate alcohols
with either homogeneous or heterogeneous catalysts.z,y Carbo-
hydrate alcohol a-Glc-13 was treated with carbohydrate amine
a-Glc-12 under the reaction conditions used in Scheme 2, but the
coupling product was not formed. In this case, the addition
of an inorganic base resulted in a significant improvement. With
NaHCO3 (25 mol%) at 160 1C, the reaction gave a secondary
amine product (Glc,Glc-14), a pseudodisaccharide, in 66% yield.
With Cs2CO3, we saw a further improvement, and the secondary
amine was formed more quickly at a lower temperature (120 1C)
and in higher yield (Scheme 4). This result contrasts again with
the observations of Fujita et al. in the coupling of anilines
with benzylic alcohols, where better results were obtained with
The reactivity of primary carbohydrate alcohols and the
unreactive nature of secondary carbohydrate alcohols suggest
the possibility of a regioselective amination reaction. Hence
the diol b-Glc-18 with free OH4 and OH6 was treated with
amine a-Glc-12 under the coupling reaction conditions with
Cs2CO3, and a single pseudodisaccharide product (Glc,Glc-19)
due to amination of the primary hydroxyl was seen (Scheme 5).
Based on these results, it is possible to draw some provisional
conclusions about the behaviour of carbohydrates in the
transition-metal-catalysed reaction between alcohols and amines.
All products were isolated as single diastereomers. Epimerisation
of secondary carbohydrate alcohols was not observed under
these conditions, and neither was epimerisation detected at the
centres vicinal to the presumed intermediate carbonyl.6 This
latter observation contrasts with an earlier result on a protected
glycerol.9d Carbohydrate amines can be alkylated in the presence
of unprotected carbohydrate hydroxyl groups, using non-
carbohydrate alcohols as alkylating agents. The primary alcohol
of a carbohydrate is more readily functionalised than the
secondary alcohols, which allows regioselective functionalisation.
The amination of carbohydrate alcohols requires addition of a
Scheme 4 Synthesis of pseudodisaccharides by amination of primary carbohydrate alcohols.
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base, whereas for non-carbohydrate alcohols a base is not
required. Cs2CO3 gave good results for the functionalisation of
primary carbohydrate alcohols.
We envisage that the methods for the synthesis of structural
variants of N-substituted aminosugars described in this
communication could find numerous applications in the
optimisation of structures for a given purpose, e.g. as ligands
for biomolecules. Synthetic N-substituted carbohydrate
amines have been shown to inhibit glycosidases;18 and it has
been suggested that they could act as ligands for RNA.19
Modification of the structure of natural aminoglycosides could
lead to new antibiotics.20
IC and BMM thank Vetenskapsradet, and BMM thanks the
Exselent centre for support. KEB was supported by a Marie
Curie fellowship. SA is supported by the Wenner-Gren
foundation.
Notes and references
z We found that other organometallic complexes that have been
reported for the amine–alcohol redox condensation failed to give good
results with carbohydrate alcohols (amongst others, Ru(p-cymene)-
dppf, K2CO39d and Ru3(CO)12, P(o-tol)310b), giving either no reaction
at all, or traces (o 5%) of the aminated product. For the reaction
between carbohydrate amines and non-carbohydrate alcohols, some
reactivity was seen using Ru(p-cymene)dppf, K2CO3, toluene, 4 A sieves,
120 1C, 36 h: amine a-Glc-12 and n-butanol gave the corresponding
tertiary amine (65%), but this system was not investigated in detail.
y Oxidation of the anomeric hydroxyl of hemiacetals or of primary
alcohols by hydrogen-transfer to form lactones has been demonstrated
using ruthenium21 and rhodium22 catalysts with partially protected or
unprotected carbohydrates or alditols as substrates. Reaction of
secondary hydroxyl groups is most unusual.17,21d
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c
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Chem. Commun., 2011, 47, 7827–7829 7829