Dimroth-type rearrangement of 1-benzyl- and 1-glycosyl-5-aminoimidazoles to 4-(N-substituted amino)imidazoles

Article abstract of DOI:10.1016/j.tetlet.2011.11.058

An efficient route is described to an unusual exocyclic 4-β-d-ribofuranosyl-aminoimidazole nucleoside, related 4-N- benzylaminoimidazoles and imidazole analogues of precursors in the de novo biosynthesis of purines, via a regiospecific and stereoselective

Full text of DOI:10.1016/j.tetlet.2011.11.058

Tetrahedron Letters 53 (2012) 412–415
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dimroth-type rearrangement of 1-benzyl- and 1-glycosyl-5-aminoimidazoles
to 4-(N-substituted amino)imidazoles
Stefano Costanzi, Sean P.N. Rouse, Laurence Vanbaelinghem, Timothy J. Prior, David F. Ewing,
⇑
⇑
Andrew N. Boa , Grahame Mackenzie
Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route is described to an unusual exocyclic 4-b-D-ribofuranosyl-aminoimidazole nucleoside,
Received 12 October 2011
Revised 2 November 2011
Accepted 11 November 2011
Available online 22 November 2011
related 4-N-benzylaminoimidazoles and imidazole analogues of precursors in the de novo biosynthesis
of purines, via a regiospecific and stereoselective base-catalysed Dimroth-type rearrangement of 1-ribo-
furanosyl and 1-benzyl-5-aminoimidazoles. Use of a 15N labelled precursor showed the unequivocal
endo- to exocyclic translocation of the nitrogen atom during the rearrangement.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Exocyclic nucleoside
Dimroth rearrangement
Imidazole
Exocyclic amino nucleosides have been known for many years.
However, when clitocine (1, Fig. 1) was isolated1 from the mush-
room Clitocybe inversa in 1986, it stimulated an increased interest
in such types of compounds due to the range of biological proper-
ties that it exhibits.2 Clitocine shows potent insecticidal activity
against Pectinophora gossyiella.1 Further studies showed that it also
displays inhibitory activity against adenosine kinase and has anti-
tumor activity in vitro against a range of cell lines.3 More recently,
the apoptotic effect of clitocine on L1210 cells was also described4
and it has since been found that it induces apoptosis in human cer-
vical cancer cells by multiple pathways including death receptor
and mitochondrial pathways.5
intermediates in the Traube synthesis of purines.8 In contrast to
synthesising exocyclic amino nucleosides by either (i) condensation
of an amino sugar with an activated heterocyclic base, (ii) reaction
of an exocyclic amino group of a heterocyclic base with a suitably
activated sugar, or (iii) cleavage of the imidazole ring of purine
nucleosides, an alternative approach has been by rearrangement.
For example, 6-cyano-9-b-D-ribofuranosylpurine is converted by
rearrangement to give 4-amino-8-(b-
D-ribofuranosylamino)-pyr-
imidino[5,4-d]pyrimidine (2, Fig. 1).9
Despite all the interest in exocyclic nucleosides, relatively few
imidazole or related azole examples of such compounds have been
synthesised. Examples reported include the exocyclic 5-aminothia-
zole-4-carboxamide and 4-carboxylate nucleosides 3 and 4 (Fig. 1),
synthesised by Vorbrüggen glycosidation of the exocyclic amino
Clitocine (1) has been synthesised by two routes. The first
involved displacement of a chlorine atom of 4,6-dichloro-5-nitro-
pyrimidine with either 2,3,5-tribenzoylribofuranosylamine or 2,
group with 10-O-acetyl-20,30,50-tri-O-benzoyl-
Aminoimidazole-4-carboxamide was found to react directly with
-ribose in methanol to give a complex mixture of anomeric pairs
D
-ribofuranose.10 5-
3-O-isopropylidene-
of clitocine (1) involved condensing 4,6-diamino-5-nitropyrimidine
D
-ribofuranosylamine.3,6 The second synthesis
D
with 1-O-acetyl-2,3,5-tri-O-benzoyl-
D
-ribofuranose using Vorbrüg-
of both furanose and pyranose imidazole exocyclic amino nucleo-
sides 5 which were detected by NMR spectroscopy but not
isolated.11 In contrast, 5-aminoimidazoles normally glycosylate at
either of the ring nitrogen atoms to give mixtures of N-1 and N-3
regioisomers when condensed with a protected sugar activated at
the anomeric position.12–14 To our knowledge, no evidence has been
reported for glycosylation at the exocyclic amino group of 5-amino-
imidazole-4-carboxylic acid derivatives in such reactions. In a
preliminary report,15 we described the synthesis of the exocyclic
b-5-aminoimidazole nucleoside 6a ( Fig. 1) by a Dimroth-type
gen conditions to obtain a higher yield of the target product.6 Exo-
cyclic amino pyrimidine nucleosides have also been synthesised
by ring-opening of the imidazole ring of purine nucleosides. For
example, cleavage of the imidazole ring of 7-methylguanosine with
aqueous ammonia was used to synthesise 2-amino-6-hydroxy-5-
(N-formyl-N-methylamino)-4-(D
-ribofuranosylamino)pyrimidine.7
A large number of exocyclic amino pyrimidine nucleosides and
related compounds have been synthesised in a similar manner as
rearrangement of the 1-b-D-ribofuranosylated 5-aminoimidazole
nucleoside 7a in the presence of hydroxide ions. The b-anomeric
⇑
Corresponding authors.
E-mail addresses: a.n.boa@hull.ac.uk (A.N. Boa), g.mackenzie@hull.ac.uk
integrity was maintained throughout the rearrangement. Related
(G. Mackenzie).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.058

S. Costanzi et al. / Tetrahedron Letters 53 (2012) 412–415
413
O
NH2
N
a
e
b
d
HON
R1
CN
H2N
R1
CN
EtO
N
N
R1
CN
N
NO2
NH
N
S
R
N
N
N
13
12
11
N
O
NH
NH
HO
HO
HO
O
O
c
I
Me
N
OH OH
1
clitocine
OH OH
OH OH
3 R = NH2
4 R = OEt
Me
R1
R1
R1
O
N
2
*
*
*
N
N
HN
NH2
NH2
NH2
R2
R2
R2
O
O
14
7
10
Me
N
OEt
NH2
Me
N
OEt
NH
O
R1
R2
O
I
N
N
N
O
f
NH2
TrO
TrO
TrO
O
14N
N
H
a
CO2Et
NH
R
Me
N
R1
O
O
O
O
O
O
5
6a
7a
N
*
NH
b
c
d
e
CONH2
CN
PhCH2
PhCH2
PhCH2
PhCH2
O
R = α/β-D ribofuranosyl
and α/β-D ribopyranosyl
14N
14N
14N
15N
R2
6
H
N
OHC
Me
CO2Et
CO2Et
R
Me
R
N
R
HN
N
O
O
I
P
O
NH2
CH2Ph
N
NH
HO
OH
HO
N
14N
f
CO2Et
CH2Ph
OH OH
8 R = O (FGAR)
6b R =CO2Et
6c R =CN
7b R =CO2Et
7c R =CN
O
O
9 R = NH (FGAM)
Figure 1. The exocyclic amino nucleoside clitocine (1) and related hetereocycles.
CON
14N
g
PhCH2
Scheme 1. Reagents and conditions: (a) Na2S2O4/H2O or Al–Hg/H2O; (b) (EtO)3CH,
MeCN, ; (e) 2 M NaOH/EtOH, rt; (f) 2 M
; (c) R2NH2, MeCN; (d) MeI, MeCN,
NaOH/MeOH, or CsF/DMF, heat.
rearrangements of 1-benzyl-3-methyl-5-aminoimidazole-4-car-
boxamide (7b) and its nitrile derivative 7c to give the exocyclic imi-
dazoles 6b and 6c, respectively, have been reported by Sen et al.16
Fujii also prepared these compounds as intermediates in the synthe-
sis of 3,7-dialkylxanthines and 1,3,7-dialkylxanthines via ring-
opening of the pyrimidine ring of 3,7-dialkyladenine quaternary
ammonium salts.17,18 However, such a route would not lend itself
to the synthesis of exocyclic 5-aminoimidazole nucleosides due to
the instability of related 3-glycosylated adenines. We now report a
more comprehensive study of the Dimroth-type rearrangement of
5-aminoimidazoles involving the use of 15N labelled intermediates.
We also show how this method can be used to synthesise the exocy-
clic 5-aminoimidazole nucleoside 6a, and also 14a (Fig. 1), an ana-
logue of FGAR (8) and FGAM (9) which are intermediates in the de
novo purine nucleotide biosynthetic pathway.
D
D
D
10c by dehydration of the amide 10b with POCl3 in CH2Cl2. Alter-
native routes to 10c have involved direct condensation of a benzyl
halide with 5-aminoimidazole-4-nitrile to give a mixture of N-1
and N-3 regioisomers.28,29
In previous studies19,30 we quaternised the imidazoles 10d and
10f, respectively, at N-3 with methyl iodide to obtain the quater-
nary compounds 7d and 7f, respectively, and found them to be
labile to base-catalysed ring opening30 but the nature of the prod-
ucts was not established. Therefore, in light of the work reported
by Sen16 to obtain 5-benzylamino-3-methylimidazoles 6b and 6c
it was of interest to investigate such reactions in greater detail
and explore the opportunity to provide an effective route to imid-
azole exocyclic amino nucleosides. Ethyl 5-amino-1-benzylimida-
zole-4-carboxylate (10d) was readily methylated under relatively
mild conditions with methyl iodide in acetonitrile to give the imi-
dazolium salt 7d19 with an optimum yield of 95%. Under the
aforementioned conditions the 5-amino-1-benzylimidazole-4-car-
boxamide was not successfully quaternised. This was presumed to
be due to possible hydrogen bonding between N-3 and either the
amide or amine groups at positions 4 and 5 of the imidazole ring,
respectively. Further support for this suggestion was provided by
the readiness of the analogous tertiary amide 10g and the nitrile
10c to methylate with methyl iodide to give the imidazolium salts
7g and 7c respectively, in reasonable yields. Sen16 showed that the
amide 10b could, however, be quaternised under more forcing
conditions, fusion of 10b with methyl toluene-4-sulfonate at high
temperature to afford 7b as the sulfonate salt in a 47% yield.
To investigate further the hydrogen bonding of 10b in the solid
state, a sample was recrystallised from methanol to provide
The full route to the 4-N-substituted aminoimidazoles 6 is
shown in Scheme 1. The starting 1-substituted 5-aminoimidazoles
10b, 10d,19 10e, 10f20,21 and 10g used in this work were synthes-
ised in accordance with the Shaw method22 which permits regio-
specific control in the introduction of substituents on the
imidazole ring. Thus, benzylamine, 15N-labelled benzylamine and
2,3-O-isopropylidene-
with the appropriate imidate 11b,21,23 11d21,23 or 11g, obtained
from triethyl orthoformate and either -amino- -cyanoacetamide
(12b),21,23,24 ethyl -cyanoacetate (12d)21,23,24 or
-amino- -ami-
no- -cyanoacetylpiperidine (12g), respectively. Compound 13g
D
-ribofuranosylamine20 were each reacted
a
a
a
a
a
a
was obtained by reaction of an acidic solution of 1-cyanoacetylpi-
peridine25 with amyl nitrite. Alternative routes reported by others
to obtain 10b are not regiospecific. They involve cyclisation of
a-
formamido-N-benzylguanylacetamide26 and direct condensation
of benzyl chloride and 5-aminoimidazole-4-carboxamide in the
presence of KOH and DMF.27 We synthesised the related nitrile

414
S. Costanzi et al. / Tetrahedron Letters 53 (2012) 412–415
crystals suitable for diffraction studies. The crystal structure31 of
10b reveals sheets held together by hydrogen bonds between the
imidazole N-3 and the 4-carboxamide and 5-amino groups in
neighbouring molecules (Fig. 2A). Above and below these sheets
project the phenyl groups and these are suitably close to suggest
involving direct condensation of an aglycone with a glycone. In
the hope of obtaining the acyclic intermediate 14f, compound 7f
was reacted with hydroxide. Unfortunately, a complex mixture of
products was obtained which was not resolved and attempts to
recyclise to give the exocyclic amino nucleoside 14f were unsuc-
cessful. In contrast, similar reaction with the analogous N-1-benzyl
imidazole ester 7d with NaOH cleanly gave the acyclic product 14d
as a mixture of rotamers. Cyclisation of 14d to the C-4 benzylamino
imidazole 6d was effected in reasonable yield by heating in an eth-
anolic solution of NaOH. Similar success was observed in the base-
catalysed Dimroth rearrangements of the quaternised 4-nitrile 7c
and 4-tertiary amide 7g to give the 4-N-substituted aminoimidaz-
oles 6c and 7g, respectively. It seemed possible therefore that the
problems associated with converting 7f to 6f were due to 7f forming
a 50-O-alkoxide ion and intramolecular reaction with the b-orien-
tated aglycone moiety under the base-catalysed ring-opening con-
ditions. To avoid such a process 7f was reacted with trityl chloride
in pyridine to give the 50-O-trityl protected derivative 10a. Methyl-
ation of 10a with methyl iodide in acetonitrile gave the imidazolium
salt 7a in a 96% yield and reaction with aqueous sodium hydroxide
gave the acyclic product 14a in good yield (67%). Compound 14a
could be regarded as a nucleoside analogue of FGAR and FGAM.
Treatment of 14a with 2 M sodium hydroxide (1 mol equiv) in eth-
anol gave the Dimroth-type rearrangement product 6a in a 68%
yield. Throughout the rearrangement the b-anomeric configuration
there are C–Hꢀ ꢀ ꢀ
p interactions between them ( Fig. 2B). Our
assumption that intermolecular interactions in 10b are the cause
of its reluctance to methylate under mild conditions therefore
seems to be borne out. The asymmetric unit of 10b contains two
independent molecules in very similar environments. The only sig-
nificant difference between the two symmetry independent mole-
cules is the orientation of the phenyl group. The two molecules
differ by 43.2° in the rotation about the C–C benzyl bond. For each
molecule the N-3 nitrogen forms two rather long, intermolecular,
hydrogen bonds to NH2 groups (one to the carboxamide, one to
the amino) as illustrated in Figure 2A. For the two N-3 nitrogen
atoms the Nꢀ ꢀ ꢀH–N distances are 2.38/2.61 Å and 2.39/2.64 Å.
Using our mild alkylating conditions to form imidazolium salts,
the b-D-ribofuranosylimidazole nucleoside 10f was converted into
the quaternary salt 7f. We envisaged using this salt as a starting
material for the synthesis of exocyclic aminonucleosides via an ana-
logue of FGAR (8) or FGAM (9). Such types of compounds would not
be readily obtained by traditional nucleoside synthesis strategies
was retained and no
a-anomers of either 14a or 6a were detected in
the reaction mixtures.
In order to confirm the rearrangement of the N-1 ring nitrogen
to the C-4 amino group, it was decided to synthesise an 15N-1 ana-
logue of 7d, namely 7e, to follow the course of the labelled atom
through the rearrangement. Thus, 10e was synthesised in a similar
manner to 10d but starting with 15N-benzylamine (containing 10%
15N and 90% 14N). In deuterochloroform the 15N chemical shift of
the labelled atom (N-1) in 10d was ꢁ221.55 ppm. After methyla-
tion of the imidazole, cleavage of the imidazole ring in 7e was
achieved in a 82% yield with aqueous sodium hydroxide solution
to give 14e which was obtained as the Z-geometric isomer. The
15N chemical shift of the labelled nitrogen atom in 14e was now
observed at ꢁ289.43 ppm. Cyclisation of 14e to give the C-4 ben-
zylamino derivative 6e was catalysed with CsF in DMF. The use
of CsF in DMF resulted in a higher yield (72%) of the cyclised prod-
uct 6e over that obtained (53%) using 2 M sodium hydroxide
(1 mol equiv) in ethanol in a parallel study. The rearranged product
6e revealed an 15N chemical shift of ꢁ312.82 ppm for the labelled
benzylamino nitrogen atom. If reaction samples were analysed
during the course of the cyclisation, the change in chemical shift
of the labelled atom from ꢁ289.43 in 14e to ꢁ312.82 ppm in 6e
could be followed.
In conclusion we have used an 15N labelled precursor to show
the endo- to exocyclic translocation of the N-1 nitrogen atom
during the base-catalysed Dimroth-type rearrangement of 5-ami-
no-1-benzyl-4-ethoxycarbonyl-3-methylimidazolium iodide (7e).
In a similar fashion the exocyclic 4-b-D-ribofuranosyl-aminoimi-
dazole nucleoside 6a can be made by stereoselective rearrange-
ment of 1-ribofuranosylimidazolium salt 7a via the acyclic
product 14a which may be regarded as an analogue of FGAR (8)
and FGAM (9). Clean methylation of the primary amide 10b to form
7b could not be achieved in the same fashion as 10e and 10a, but
was possible using cyano (10c) and tertiary amide (10g) deriva-
tives. Rearrangement of the resulting salts, 7c and 7g, respectively,
yielded interesting analogues 6c and 6g of the aglycone unit of 6a.
Acknowledgments
Figure 2. (A) Hydrogen bonding of the N-3 nitrogen within the crystal structure of
10b. (B) Asymmetric unit of the crystal structure of 10b with atoms drawn as 50%
thermal ellipsoids.
We thank the EPSRC (SPNR) and the University of Hull for
funding.

S. Costanzi et al. / Tetrahedron Letters 53 (2012) 412–415
415
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data for 10b at 150 K and 363 K, respectively. These data can be obtained free
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Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
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Supplementary data
Supplementary data (experimental procedures and compound
characterisation data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.11.058.
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