Groebke-Blackburn-Bienaymé multicomponent reaction in scaffold-modification of adenine, guanine, and cytosine: Synthesis of aminoimidazole-condensed nucleobases

Article abstract of DOI:10.1016/j.tetlet.2010.10.143

A multicomponent method for scaffold-modification of nucleobases (adenine, guanine, and cytosine) was developed. This modification approach, as an alternative to usual synthetic routes involving protection-deprotection or S_NAr of halo (or leavi

Full text of DOI:10.1016/j.tetlet.2010.10.143

Tetrahedron Letters 52 (2011) 56–58
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Tetrahedron Letters
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Groebke–Blackburn–Bienaymé multicomponent reaction in
scaffold-modification of adenine, guanine, and cytosine: synthesis
of aminoimidazole-condensed nucleobases
⇑
Sankar K. Guchhait , Chetna Madaan
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062 Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A multicomponent method for scaffold-modification of nucleobases (adenine, guanine, and cytosine) was
developed. This modification approach, as an alternative to usual synthetic routes involving protection–
deprotection or SNAr of halo (or leaving group-equivalent)-purines, affords in one step therapeutically-
relevant substituted aminoimidazole-[i]-condensed adenine, [b]-condensed guanine, [c]-condensed
cytosine. These derived nucleobases possess enhanced lipophilicity and solubility and contain the func-
tionalities useful for further chemical manipulations.
Received 17 September 2010
Revised 25 October 2010
Accepted 27 October 2010
Available online 4 November 2010
Keywords:
Nucleobases
Ó 2010 Elsevier Ltd. All rights reserved.
Fused nucleobases
Multicomponent reaction
Cycloaddition
The modification/functionalization of nucleobases is important,
because the derived products display a wide range of biological
activities,1 for example, agonist/antagonist effects to receptors2
(such as adenosine and corticotropin-releasing hormone), inhibi-
tion of enzymes3 (such as kinases, HSP90, sulfotransferase, and
phosphodiesterases), tubulin polymerization,4 DNA-stabilization5,
and cellular dedifferentiation.6 Furthermore, they are valuable as
chemical biology tools. The modification/incorporation of substitu-
tions in purines is generally made at positions 2, 6, 8, and/or 9.
Since purines contain multiple amine functionalities, these modifi-
cations usually necessitate the use of protection–deprotection
chemistry7 or directing groups8 (Scheme 1, approach A). As an
alternative route, the modifications are carried out by SNAr of halo
(or leaving group-equivalent)-purines which are generally pre-
pared from xanthine/adenine in multi-step process (Scheme 1, ap-
proach B).3a,9 While the substitutional modification of nucleobases
is common, scaffold-modification toward the synthesis of their
heterocyclic-fused3c,d,10 and heteroaromatic-fused analogs3e,11 is
little known. Recently, Hocek and co-workers11 introduced an
approach of modification at C8–N9 of adenine and 6-methylpurine
toward the synthesis of purino[8,9-f]phenanthridines. The
approach involves the consecutive reactions of N9-arylation of
purines (which eventually blocks N9) with 2-bromophenylboronic
acid, Suzuki coupling, and the intramolecular C8–H arylation. We
report herein an unprecedented one-step direct scaffold-modifica-
tion of adenine, guanine, and cytosine by a multicomponent reac-
tion (Scheme 1). This affords the preparation of aminoimidazole-
condensed nucleobases through the incorporation of therapeuti-
cally-relevant substituted aminoimidazole at N6–N1 in adenine,
N2–N3 in guanine, and N1–N6 in cytosine, respectively. This mod-
ification converts the hydrogen bond donor–exocyclic amine in
nucleobases into its acceptor counterpart and introduces one
hydrogen bond donor–amine and an alkyl/aryl substituent in
N-fused imidazole ring. These derived nucleobases possess
enhanced lipophilicity and solubility and contain the functional-
⇑
Corresponding author.
E-mail address: skguchhait@niper.ac.in (S.K. Guchhait).
Scheme 1. General approaches for selective structural modifications in nucleobases.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.143

S. K. Guchhait, C. Madaan / Tetrahedron Letters 52 (2011) 56–58
57
Table 2
ities useful for further chemical manipulations. This modification
Synthesis of aminoimidazole-fused nucleobasesa
approach is thus potentially important in drug discovery research.
Multicomponent reactions (MCRs) offer the elegance of one-pot
reaction, atom-, structural- and bond-forming economy, and the
feasibility of introducing maximum diversity elements in one
chemical event operation.12 As part of our continuing program to
explore the multicomponent methods toward the preparation of
therapeutically-relevant heterocycles,12a,13 we investigated the di-
rect modification of nucleobases. Based on the structural features
of adenine, guanine, and cytosine comprising 2-amidine function-
ality, we speculated that the Groebke–Blackburn–Bienaymé multi-
component reaction (GBB MCR)13,14 of these nucleobases with
aldehyde and isocyanide could afford the incorporation of N-fused
aminoimidazole. In an initial experiment, a reaction of adenine
with 4-chlorobenzaldehyde and tert-butylisocyanide was per-
formed following our developed protocol13b for the GBB MCR cat-
alyzed by ZrCl4 in polyethylene glycol at 50 °C. However, the
reaction even after 18 h virtually failed leaving adenine, aldehyde,
and isocyanide almost intact (Table 1). Increasing the reaction tem-
perature to 70 °C has led to enhanced conversion with the desired
product in 41% isolated yield. Further increasing the temperature
did not improve yield. When performed in MeOH, the reaction
did not take place. As it is well-known that the notorious low sol-
ubility of pure purines in many solvents impedes their structural
modifications, we focused on finding a suitable reaction solvent
along with a catalyst. A series of experiments were then carried
out with various catalysts in different solvents. The optimized
yields were obtained utilizing adenine (1 mmol), aldehyde
(1 mmol), isocyanide (1 mmol), ZrCl4 (10 mol %), and DMSO as sol-
vent (3 mL) at 70 °C. In every case, reaction conversion was not
complete. DMSO was found to be a more effective solvent than
PEG-400, MeOH, ethylene glycol, or DMSO–H2O; while DMF and
DMA showed similar efficacy as DMSO. A survey of various Lewis
and Brønsted acid catalysts (ZrCl4, CeCl3Á7H2O, InCl3, Sc(OTf)3,
and HClO4) revealed ZrCl4 to be the most effective. Aqueous-
extraction of the crude reaction mixtures caused the loss of prod-
ucts because of their partial solubility in water. Direct column
chromatographic purification after partial evaporation of DMSO
of crude reaction mixture was thus performed and it resulted in
Entry
1
Aminoimidazole-fused nucleobasesb
Time (h)
7.5
Yieldc (%)
68
2
3
4
6.5
63
51
60
7
8
5
6
7
6
72
64
Table 1
Standardization of method
7
8
9
7.5
57
50
50
NHtBu
NH2
H
N
N
Catalyst (10 mol%)
N
Cl
OHC
Cl
N
N
Solvent (3 mL)
70ºC
HN
8
N
N
N
NC
Entry
Catalyst
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
PEG-400
PEG-400
PEG-400
MeOH
Traceb
41
42c
0
35
68
62
60
23
42
47
52
43
8
Ethylene glycol
DMSO
DMF
DMA
10
11
7
8
25
15
DMSO/H2O (1:1)
DMSO
CeCl3Á7H2O
InCl3
DMSO
DMSO
DMSO
Sc(OTf)3
HClO4
a
b
c
Isolated yields.
Reaction was carried out at 50 °C.
Reaction was carried out at 90 °C.
(continued on next page)

58
S. K. Guchhait, C. Madaan / Tetrahedron Letters 52 (2011) 56–58
Table 2 (continued)
References and notes
Entry
Aminoimidazole-fused nucleobasesb
Time (h)
6
Yieldc (%)
52
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a
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increased yield. We then examined the scope of this method for the
multicomponent reactions of adenine, guanine, and cytosine with
various aldehydes and isocyanides (Table 2).15 These reactions fur-
nished corresponding substituted aminoimidazole-[i]-condensed
adenine (Table 2, entries 1–9), [b]-condensed guanine (Table 2, en-
tries 10 and 11), [c]-condensed cytosine (Table 2, entries 12–14) in
moderate to good yields. The products were characterized by 1H
and 13C NMR, mass and IR spectroscopies, and confirmed by CHN
analysis or HRMS. Guanine is known as notoriously difficult-to-
protect/modify because of its very poor solubility in almost all
common solvents (including water) and its multi-functional/struc-
tural nature (imidazole, amide, and guanidine). With the present
method guanine was found to undergo modification albeit in low
yields (Table 2, entries 10 and 11). The reactions of guanine were
found to be incomplete even by increasing the reaction tempera-
ture or prolonging the reaction. Since a wide range of aldehydes
are commercially available and various isocyanides are accessible,
this synthetic approach can produce diverse-substituted N-fused
aminoimidazole-purines and cytosine derivatives. The modified
nucleobases can undergo the post modification at free amines
(N9 for adenine and guanine and N1 for cytosine). The tolerance
of halogen (Cl and Br) and alkene functionalities in the method
provides the opportunity of their various further chemical manip-
ulations. Thus, the modification of nucleobase-motifs in this ap-
proach and the possible post-chemical manipulation by usual
methods can offer a library of heteroaromatic-fused nucleobases
and nucleosides.
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ˇ
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(b) Colombo, M.; Peretto, I. Drug Discov. Today 2008, 13, 677–684; (c) Dömling,
A. Chem. Rev. 2006, 106, 17–89.
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14. GBB MCR was first reported in 1998 by three independent research groups,
Groebke, Blackburn and Bienaymé (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett
1998, 661–663; (b) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635–3638; (c) Bienaymé, H.; Bouzid, K. Angew.
Chem., Int. Ed. 1998, 37, 2234–2237.
15. Representative synthesis of N-tert-Butyl-8-(4-chlorophenyl)-3H-imidazo[1,2-
i]purin-7-amine (Table 2, entry 1): To a mixture of adenine (0.27 g, 2 mmol)
and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in DMSO (5 mL), tert-butyl
isocyanide (0.17 g, 2 mmol) and ZrCl4 (47 mg, 10 mol %) were added. The
mixture was allowed to stir at 70 °C under open air. After 7.5 h of reaction
(monitored by TLC), DMSO was partially removed from the resultant mixture
by rotary evaporation under reduced pressure (2 mm Hg) at 50–60 °C (water
bath temperature). The direct column chromatographic purification of crude
product over silica gel (mesh size: 60–120) eluting with EtOAc–hexane
In conclusion, we have developed a method for the unprece-
dented scaffold-modification of adenine, guanine, and cytosine
into their aminoimidazole-condensed derivatives. Owing to the
therapeutic relevance of the structural modification and the sim-
plicity of the method, being one-step and multicomponent in nat-
ure and alternative to usual multi-step synthetic routes involving
protection–deprotection or SNAr, this method may find potential
application.
afforded
N-tert-butyl-8-(4-chlorophenyl)-3H-imidazo[1,2-i]purin-7-amine
(0.462 g, 68%); faint yellowish white solid; mp = 229–231 °C; MS (APCI) m/z:
341 (MH+); HRMS (m/z) calcd for C17H17ClN6 341.1281 (MH+), found 341.1275;
1H NMR (400 MHz, DMSO-d6): d 1.02 (s, 9H), 4.80 (s, NH), 7.48 (d, J = 8.4 Hz,
2H), 8.21–8.24 (m, 3H), 9.02 (s, 1H). 13C NMR (100 MHz, DMSO-d6): d 29.8,
55.7, 123.9, 128.0, 129.3, 131.6, 133.5, 134.5, 135.3, 139.6. IR (KBr)
3567, 1642, 1486, 1375, 1319, 1196, 1090, 1013 cmÀ1
Anal. Calcd for
17H17ClN6: C, 59.91; H, 5.03; N, 24.66. Found: C, 59.67; H, 5.06; N, 24.98.
mmax = 3650,
.
C
3-(tert-Butylamino)-2-(4-chlorophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one
(Table 2, entry 12):Yellowish white solid, mp = 222–224 °C; MS (APCI) m/z: 317
(MH+); 1H NMR (400 MHz, DMSO-d6): d 0.96 (s, 9H), 2.98 (s, NH), 4.58 (s, NH),
6.45 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 8.10 (d,
J = 8.4 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): d 29.8, 57.5, 98.3, 128.4, 129.2,
Acknowledgment
129.4, 129.6, 131.6, 133.3, 134.1, 142.9, 149.2. IR (KBr) mmax = 3337, 3096, 1707,
We gratefully acknowledge financial support from DST, New
Delhi for this investigation.
1546, 1486, 1363, 1305, 1193, 1088 cmÀ1. Anal. Calcd for C16H17ClN4O: C,
60.66; H, 5.41; N, 17.69. Found: C, 60.28; H, 5.56; N, 18.01.