Synthesis of purines and other fused imidazoles from acyclic amidines and guanidines

Article abstract of DOI:10.1021/ol0504751

(Chemical Equation Presented) Purines, xanthines, and other fused imidazoles can be prepared from amidines or guanidines, with retrosynthetic disconnection at the ring fusion. Ring closure proceeds using Cu(I), with no special ligands required. The method allows for easy modification of the heterocyclic nucleus and is tolerant of functionality pendant to the ring system.

Full text of DOI:10.1021/ol0504751

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1833-1835
Synthesis of Purines and Other Fused
Imidazoles from Acyclic Amidines and
Guanidines
Bruce G. Szczepankiewicz,* Jeffrey J. Rohde, and Ravi Kurukulasuriya
Metabolic Disease Research, Global Pharmacuetical Research and
DeVelopment Organization, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-6098
bruce.szczepankiewicz@abbott.com
Received March 4, 2005
ABSTRACT
Purines, xanthines, and other fused imidazoles can be prepared from amidines or guanidines, with retrosynthetic disconnection at the ring
fusion. Ring closure proceeds using Cu(I), with no special ligands required. The method allows for easy modification of the heterocyclic
nucleus and is tolerant of functionality pendant to the ring system.
The purine nucleus is found in a wide variety of biologically
active molecules including nucleotides, enzyme cofactors,
intracellular second messengers, and pharmaceutical agents.1
Methods for preparing analogues of these important mol-
ecules generally rely on substitution of the intact purine ring
system. However, modification of the core is not a straight-
forward process, and the preparation of alternate heterocyclic
systems often requires harsh reaction conditions that do not
tolerate much functionality about the ring system. One
retrosynthetic disconnection that would allow a high degree
of variability within the core is formation of the imidazole
ring (B ring) after assembly of any desired A ring (Figure
1). During the course of a program to prepare novel inhibitors
imidazole ring systems and occurs under milder conditions
than traditional methods for preparing these molecules.
The xanthine system is a well-known scaffold for biologi-
cally active molecules, e.g., caffeine. We wished to prepare
xanthine mimetics with an amine substituent at the 8-position,
but available methods required the use of a large excess of
amine and extended heating times for introduction of this
substituent3 (Scheme 1). Guanidines such as Boc-aminopi-
Scheme 1. Traditional Substitution of Purine 8-Position
peridine 1 are readily available in high yield via substitution
of N-pyrazinylguanidine hydrochloride.4 If these could be
Figure 1. Disconnection of the purine nucleus at the ring fusion.
(1) (a) Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson,
J. D. Molecular Biology of the Cell, 3rd ed.; Garland: New York, 1994; p
736. (b) Gao, Z.; Duhl, D.; Harrison, S. D. Ann. Rep. Med. Chem. 2003,
38, 193.
of dipeptidyl peptidase IV,2 we discovered an approach of
this nature. The reaction is widely applicable to fused
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Table 1. Fused Imidazole Systems Prepared from Acyclic Guanidines and Amidinesa
a Experimental procedures for the preparation of these amidines and fused imidazoles can be found in the Supporting Information. b Reactions were run
in THF or dioxane solution at ca. 0.1 M substrate with 5 equiv of NaH and 5 mol % of CuI. For most substrates, 30 min at 65 °C was sufficient to effect
complete ring closure. More electron-rich substrates (entries 9, 10) required higher temperatures. c Isolated yields. Ring closures were quantitative for all
systems except entry 10 by HPLC or TLC. Some baseline material was present by TLC for entry 10. d One-pot sequence from benzamidine and dibromo-
N-methylmaleimide gave 63%. e The acyclic pyrimidinoguanidine contained some inseparable 5-chloro compound. This can be isolated following ring
closure of the bromide. f One-pot sequence gave the xanthine in 20% (unoptimized) yield.
fused to a uracil derivative such as bromide 2 under mild
conditions, it would allow for easy modification of virtually
any portion of the purine nucleus. Addition of the guani-
dine at the pyrimidine 6-position proceeded smoothly
(Scheme 2), but initial attempts to close the ring under acidic,
The same chemistry can be used to close other fused
imidazole ring systems, allowing for the easy assembly of
substituted purine analogues (Table 1). Electron-deficient
systems such as pyridazinone, quinone, and maleimide all
proceeded under similar conditions, i.e., addition-elimi-
nation of guanidine 1 followed by ring closure. Aromatic
bromides are suitable for ring closure, but chlorides do not
react.
Scheme 2. Mild Conditions for Purine 8-Substitution
The reaction also succeeds with amidines. Addition-
elimination of benzamidines to uracils followed by ring
closure gave the expected products (Table 1, entries 7, 8).
More electron-rich systems such as N-pyridylamidine or
N-phenylamidine (Table 1, entries 9, 10) were not readily
accessible via addition-elimination chemistry, so these were
prepared from arylamines and benzonitrile or butyronitrile
(see the Supporting Information for details). These systems
required higher temperatures for ring closure, but the reaction
nonetheless gave the desired product. This strategy represents
an alternative to the traditional preparation of benzimidazoles
from phenylenediamines and carboxylic acids. If the addition
reaction is run in an aprotic solvent, the second reaction can
be performed in the same vessel (Table 1, entries 4, 7). The
one-pot reaction did not succeed when the addition was
performed using ethanol and potassium ethoxide or DMF
and aq K2CO3. Although addition did occur, CuI addition
basic, or Pd-mediated conditions failed to give the desired
product. However, when guanidinobromide 3 was allowed
to stir with sodium hydride and a catalytic amount of copper-
(I) iodide at 65 °C, ring closure proceeded smoothly to give
xanthine 4.
(3) Blythin, D. J.; Kaminski, J. J.; Domalski, M. S.; Spilter, J.; Solomon,
D. M.; Conn, D. J.; Wong, S.-C.; Verbiar, L. L.; Bober, L. A.; Chiu, P. J.
S.; Watnick, A. S.; Siegel, M. I.; Hilbert, J. M.; McPhail, A. T. J. Med.
Chem. 1986, 29, 1099.
(2) Wiedeman, P. E.; Trevillyan, J. M. Curr. Opin. InV. Drugs 2003, 4,
412.
(4) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992,
57, 2497.
1834
Org. Lett., Vol. 7, No. 9, 2005

did not catalyze ring closure in these media. We tried to
extend this methodology to amides in the hope of producing
either oxazoles or indolones, but amides failed to give any
ring-closure products under the same conditions we used to
prepare fused imidazoles.
Sodium hydride was our base of choice, but alkoxides and
Cs2CO3 also promoted efficient ring closure in aprotic
solvents. Reaction rates with other bases were significantly
slower, but some ring closure was apparent with most of
the bases we explored (Table 2). In particular, KOAc (Table
aryl halides.6 The amidines and guanidines described here
react under similar conditions, though no special copper
ligands are required.
In conclusion, we have identified a general method for
the preparation of fused imidazole systems. It allows for
assembly of the ring system at the ring fusion, and the cores
can be prepared in one step from an amidine or a guanidine
and an A-ring precursor. The reaction works best on electron-
deficient ring systems, but it can be performed on more
electron-rich systems at elevated temperatures. Compared to
previous methods, it offers the advantages of easily obtained
reagents, lower temperatures, and relatively mild conditions
for the preparation of fused imidazoles. It also increases the
diversity of available starting materials, since many o-
bromoanilines are commercially available or can be prepared
in one step from the precursor anilines and aniline deriva-
tives. In most cases, the ring closure proceeds cleanly, and
pure products are obtained upon routine aqueous workup.
This is an important advantage, since many purines are
poorly soluble in common organic solvents and can be
difficult to purify. The method has proven useful for the
preparation of potent DPPIV inhibitors, and it will make the
preparation of new purines and other fused imidazole systems
simpler than is possible using previous methods.7
Table 2. Percent Ring Closure for Table 1, Entry 7 with
Various Basesa
entry
base
% product entry
base
% product
1
2
3
4
5
6
7
NaH
>99
>99
>99
>99
>99
52
8
9
K2CO3
Na2CO3
Et3N
i-Pr2EtN
NaHCO3
imidazole
none
37
35
24
18
12
<1
<1
t-BuOK
NaOEt
NaOMe
Cs2CO3
KOAc
10
11
12
13
14
K3PO4
39
a Reactions were run in dioxane at 100 °C at 0.12 M for 30 min with 5
mol % of CuI and 5 equiv of base. Each reaction was then checked by
reversed-phase HPLC, and the ratio of product to starting material was
determined by comparison with a standard curve.
Acknowledgment. We dedicate this work to Professor
Clayton Heathcock in recognition of his many contributions
to the field of organic chemistry and in honor of his academic
retirement. We also thank the R4MC and R47R scientists
for their support of this work.
2, entry 6) gave the expected product, opening the possibility
of performing the ring closure under very mild conditions
with substrates intolerant of strong bases. Dioxane, THF,
DMF, and DMSO all were suitable solvents.
The ring-closure mechanism likely follows the Cu-assisted
aromatic nucleophilic substitution pathways outlined by
Lindley.5 Copper(I) is essential for the ring closure, but
copper(I) iodide alone did not give the reaction. In recent
years, Buchwald and co-workers have explored the copper-
catalyzed coupling of different nitrogen functionalities with
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0504751
(6) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421. (b) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L.
J. Org. Chem. 2004, 69, 5578.
(7) A series of DPPIV inhibitors prepared using this methodology will
be reported soon.
(5) Lindley, J. Tetrahedron 1984, 40, 1433.
Org. Lett., Vol. 7, No. 9, 2005
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