New and practical method for synthesis of 1- and 1,3-substituted xanthines

Article abstract of DOI:10.1021/ol049272n

A new and practical method for the synthesis of 1- and 1,3-substituted xanthines is reported. Direct base-promoted condensation of the imidazole precursor 1 with carbamates 2 gives 1-substituted 7-PMB xanthines 7 in good yields. Alkylation of these derivatives or their potassium salts proceeds under mild conditions to give functionalized 1,3-substituted 7-PMB xanthines 9 in good to excellent yields. The obtained 7-PMB-protected derivatives can be readily deprotected to give the parent 1- and 1,3-substituted xanthines.

Full text of DOI:10.1021/ol049272n

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2237-2240
New and Practical Method for Synthesis
of 1- and 1,3-Substituted Xanthines
Ilia A. Zavialov,* Vilas H. Dahanukar, Hoa Nguyen, Cecilia Orr, and
David R. Andrews
Department of Synthetic Chemistry, Schering-Plough Research Institute,
1011 Morris AVenue, Union, New Jersey 07083
ilia.zaVialoV@spcorp.com
Received April 20, 2004
ABSTRACT
A new and practical method for the synthesis of 1- and 1,3-substituted xanthines is reported. Direct base-promoted condensation of the
imidazole precursor 1 with carbamates 2 gives 1-substituted 7-PMB xanthines 7 in good yields. Alkylation of these derivatives or their potassium
salts proceeds under mild conditions to give functionalized 1,3-substituted 7-PMB xanthines 9 in good to excellent yields. The obtained
7-PMB-protected derivatives can be readily deprotected to give the parent 1- and 1,3-substituted xanthines.
Functionalized xanthine derivatives comprise an important
class of pharmacologically active compounds with well-
known activity as adenosine receptor antagonists and phos-
phodiesterase inhibitors.1 The range of therapeutic applica-
tions of xanthines continues to expand and currently includes
their use in treatment of bronchial asthma and vascular
diseases and as diuretics, psychoanaleptics, and pulmonary
and cardiac stimulants.2 Despite the continued interest in
1- and 1,3-substituted xanthines as promising pharmacoph-
ores, methods for their synthesis remain scarce. The classic
Traube purine synthesis from 6-aminouracil derivatives3 and
its recent modifications4 remain rather lengthy, utilize harsh
reaction conditions, and are generally limited to the prepara-
tion of 1-primary alkyl-substituted xanthines. More recently,
alternate approaches to substituted xanthines were reported
utilizing a two-step cyclocondensation of 4-amino-5-alkoxy-
carbonylimidazoles with isocyanates5 or 4-amino-5-carbam-
oylimidazoles with phosgene equivalents.6 These methods
allow for the introduction of unhindered primary, secondary,
and aromatic substituents at N-1 and N-3; however, they
generally suffer from long reaction times, extreme temper-
atures, and the use of highly toxic, volatile reagents.
As a part of our program on PDE 5 inhibitors, we needed
a robust method to prepare multikilogram quantities of pure
(3) (a) Lister, J. H. The Purines, Supplement 1. In The Chemistry of
Heterocyclic Compounds; Taylor, E. C., Weissberger, A., Eds.; John
Wiley: New York, 1996; Vol. 54. (b) Traube, W. Ber. Deut. Chem. Ges.
1900, 33, 3035.
(4) (a) Weyler, S.; Hayallah, A. M.; Muller, C. E. Tetrahedron 2003,
59, 47. (b) Muller, C. E.; Sandoval-Ramirez, J. Synthesis 1995, 1295. (c)
Muller, C. E. Synthesis 1993, 125. (d) Vishnyakova, T. P.; Golubeva, I.
A.; Glebova, E. V. Russ. Chem. ReV. 1985, 54, 249. (e) Hutzenlaub, W.;
Pfleiderer, W. Liebigs Ann. Chem. 1979, 1847.
(5) (a) Herr, R. J.; Vogt, P. F.; Meckler, H.; Trova, M. P. J. Org. Chem.
2002, 67, 188. (b) Bridson, P. K.; Wang, X. Synthesis 1995, 7, 855. (c)
Hergueta, A. R.; Figuera, M. J.; Lopez, C.; Caamano, O.; Fernandez, F.;
Rodriguez-Borges, J. E. Chem. Pharm. Bull. 2002, 50, 1379.
(6) Itaya, T.; Ogawa, K. Tetrahedron. Lett. 1978, 32, 2907.
(1) (a) Stevanovich, V. Drug News Perspect. 1989, 2, 82. (b) Jacobsen,
K. A.; van Galen, P. J. M.; Williams, M. J. Med. Chem. 1992, 35, 407.
(2) (a) Wang, Y.; Chackalamannil, S.; Hu, Z.; Boyle, C. D.; Lankin, C.
M.; Xia, Y.; Xu, R.; Asberom, T.; Pissarnitski, D.; Stamford, A. W.;
Greenlee, W. J.; Skell, J.; Kurowski, S.; Vemulapalli, S.; Palamanda, J.;
Chintala, M.; Wu, P.; Myers, J.; Wang, P. Bioorg. Med. Chem. Lett. 2002,
12, 3149. (b) Strappaghetti, G.; Corsano, S.; Barbaro, R.; Giannaccini, G.;
Betti, L. Bioorg. Med. Chem. 2001, 9, 575. (c) Buckle, D. R.; Arch, J. R.
S.; Connolly, B. J.; Fenwick, A. E.; Foster, K. A.; Murray, K. J.; Readshaw,
S. A.; Smallridge, M.; Smith, D. G. J. Med. Chem. 1994, 37, 476. (d) Peet,
N. P.; Lentz, N. L.; Meng, E. C.; Dudley, M. W.; Ogden, A. M. L.; Demeter,
D. A.; Weintraub, H. J. R.; Bey, P. J. Med. Chem. 1990, 33, 3127.
10.1021/ol049272n CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/28/2004

Scheme 1
Table 1. Effect of Base and Solvent on Product Yield in
Reaction of 1 with 2ca
reaction conversion
solution
time,
h
of 1,
yield
of 6b, %b
entry
solvent
base
%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EtOH
iPrOH
toluene
toluene
THF
NaOEt
KOtBu
KOtAm
KOtBu
LDA
NaOMe
KOtBu
NaOMe
KOtBu
KOtBu
24
24
24
24
24
24
2
24
2
2
24
24
24
3
3
2
0
0
31
29
95
5
>99
2
>99
56
97
0
0
12
15
45
4
72
2
80
37
61
3
THF
THF
DME
DME
DEM
diglyme LHMDS
diglyme NaOMe
diglyme NaOEt
diglyme KOEt
diglyme NaOtBu
diglyme KOtBu
diglyme KOtAm
diglyme KHMDS
5
8
5
>99
98
>99
>99
>99
50
45
89
80
85
2
2
a Experimental conditions: base (15 mmol) was added to the stirred
solution of 1 (10 mmol) and 2c (12 mmol) in 50 mL of solvent at 70-80
°C, and the reaction was agitated for the specified period of time.
b Determined by HPLC assay vs analytically pure standard.
1- and 1,3-substituted 7-PMB-protected xanthines. We
reasoned that direct condensation of readily accessible7
1-PMB-4-amino-5-ethoxycarbonylimidazole precursor 1 with
commercially available carbamates 2 could, in principle,
provide an alternative and practical one-step approach to
1-substitituted 7-PMB xanthines 7 (Scheme 1). Due to the
low nucleophilicity of the pendant 4-amino group, reactions
of 1 with even the most reactive electrophiles such as
isocyanates are known to be rather sluggish.5 However, we
envisioned that, in the presence of a suitable base, the
reaction of 1 with 2 could be accelerated by simultaneous
in situ formation of highly reactive metal amide 3 and
isocyanate 4 intermediates (Scheme 1). This method has the
advantage of replacing the toxic isocyanates or phosgene
equivalents with readily available, stable carbamates. More-
over, the product of this reaction would be 1-substituted
xanthine alkali metal salt 6, which could offer practical
advantages in product isolation and make further alkylation
to produce 1,3-substituted 7-PMB xanthines 9 straightfor-
ward.
An initial screening for the optimal reaction conditions
was performed using a reaction of 1 with carbamate 2c (R1
) R2 ) Et, Scheme 1) to give product 6b (R1 ) Et, M )
K). Since 1 equiv of base was irreversibly consumed in the
formation of the product xanthine metal salt, at least 1.5 equiv
of base was used in all experiments. Our results are
summarized in Table 1. Among the solvents examined, most
promising results were obtained in ethereal solvents such as
THF, DME, or diglyme, with little or no reaction observed
in alcohols or toluene. Sodium bases such as NaOMe (entries
6, 8, 12), NaOEt (entries 1, 13), and NaOtBu (entry 15) and
unhindered potassium bases such as KOEt (entry 14)
generally gave low to moderate yields of product 6b. With
lithium bases such as LDA (entry 5) or LHMDS (entry 11),
product yields were also modest and reaction times rather
long due to slow ring closure of intermediate lithiated ureido
species 5b (R1 ) Et, M ) Li). In some of the above examples
(e.g., entries 6, 13), low overall product yields could simply
be attributed to low reaction conversions. Yet in other
instances (e.g., entries 11, 14, 15), low to moderate product
yields were obtained despite the virtually complete consump-
tion of starting imidazole 1. Careful analysis of the reaction
impurity profile and mass balance in the latter cases indicated
significant background base-promoted degradation of 1.
Fortunately, this unproductive degradation of 1 could be
appreciably minimized when strong hindered potassium bases
such as KOtBu, KHMDS, or KOtAm were employed in
diglyme (entries 16-18). To suppress the background
degradation even further, reagent addition order was modified
to slowly add a solution of base in diglyme to the preheated
(70-80 °C) agitated diglyme solution of 1 and 2c. Under
these conditions, the product potassium salt 6b precipitated
directly from reaction medium and was isolated by filtration.
A simple aqueous acid workup of isolated salt 6b delivered
the desired xanthine 7b in 80-85% isolated yields and >99%
purity.
With optimized reaction conditions in hand, we next
examined the scope and generality of this method. A variety
of 1-substituted 7-PMB-protected xanthine derivatives 7 with
primary alkyl (entries 1-5), secondary alkyl (entry 6),
tertiary alkyl (entry 7), and aromatic (entry 8) N-1 substit-
uents were prepared in good to excellent yields (Table 2).7
In the majority of cases, precipitated pure product xanthine
(7) See Supporting Information for detailed experimental procedures.
2238
Org. Lett., Vol. 6, No. 13, 2004

Table 2. Preparation of 1- and 1,3-Substituted 7-PMB Xanthines
a Yields of 1-substituted xanthines are given for the respective carbamates shown on the left in column 2.
potassium salts 6 were isolated by filtration and converted
to parent xanthines 7 on acidification. Where the product
salts did not directly precipitate (entries 5, 7, 8), isolation
and purification of 7 was achieved following a standard
acid-base workup. Reactions with O-alkyl carbamates
typically required 1.5-2.0 equiv of KOtBu for optimum
performance, while at least 3.0 equiv of KOtBu was needed
to drive the reactions with O-aryl carbamates to completion
Org. Lett., Vol. 6, No. 13, 2004
2239

due to the low basicity of in situ-generated aryloxide R2OM
(R2 ) Ar, Scheme 1), limiting its ability to further catalyze
the desired reaction. Due to their faster rate of isocyanate
generation, O-aryl carbamates offered shorter reaction times,
lower reaction temperatures, and higher product yields than
the corresponding O-alkyl carbamates with the same N-
substituent (e.g., entries 1, 2, 7, 8). In fact, the use of
O-phenyl carbamates 2j and 2l was essential to obtain good
yields of 1-tBu- and 1-Ph-substituted xanthines 7g and 7h,
respectively, as all attempts to prepare these xanthines via
condensations of 1 with the corresponding O-alkyl carbam-
ates 2i and 2k resulted in poor yields and extensive starting
material decomposition.
Scheme 2
Even with the activated O-phenyl carbamate 2j, conversion
of 1 to 7g was observed to be rather slow (∼95% after 12 h
at 70-80 °C) due to the difficult ring closure of the sterically
t
hindered ureido intermediate 5g (R1 ) Bu, M ) K).
from the two complementary deprotection protocols high-
lights the utility of the present method and makes it
potentially applicable to the preparation of a wide range of
functionalized xanthine derivatives. Alternatively, 1,3-
substituted 7-PMB xanthines can serve as convenient precur-
sors to 9-substituted purines, whereby the PMB protecting
group is removed after the N9-alkylation.9
In summary, we have developed a new and practical
approach to the preparation of both 1- and 1,3-substituted
xanthines. Direct condensation of the imidazole precursor 1
with carbamates in the presence of certain potassium bases
gives 1-substituted 7-PMB xanthines in good yields. In many
cases, product isolation is greatly simplified by formation
of its insoluble potassium salt. Further alkylation of 1-sub-
stituted 7-PMB xanthines or their potassium salts proceeds
under mild conditions in the presence of a phase-transfer
catalyst and gives a variety of functionalized 1,3-substituted
7-PMB xanthines in good to excellent yields. Among the
advantages of the new method are its experimental simplicity,
generally good yields for a variety of functionalized sub-
strates, and the use of nontoxic, readily available starting
materials. Prepared using this method, 7-PMB-protected
derivatives can be readily deprotected to give the parent
1- and 1,3-substituted xanthines.
Nevertheless, the successful preparation of 1-tertiary alkyl
xanthine 7g in good yield under these mild conditions is quite
remarkable and, to the best of our knowledge, unprecedented
in the literature.
Alkylation of 1,7-substituted xanthines at N-3 is tradition-
ally performed in DMF in the presence of an excess of
alkylating reagent and scavenger base, with reaction times
often exceeding 24 h.3a We have found that alkylation of
both xanthine potassium salts 6 and their parent xanthines 7
to form 1,3-substituted 7-PMB derivatives can be conve-
niently performed in THF or MeCN in the presence of a
phase-transfer catalyst Bu4NBr (Table 2).7 Alkylation of
isolated potassium salts 6a-d,f was particularly facile and
straightforward, producing functionalized xanthines 9a-d,f
in good to excellent yields (entries 1-4, 6). The preparation
of compounds 9e, 9g, and 9h from xanthines 7 was best
achieved in MeCN in the presence of K2CO3 and catalytic
Bu4NBr (entries 5, 7, 8). As shown by the examples in Table
2, the mild reaction conditions of this method are compatible
with a wide variety of functional groups, including acetate,
ester, nitrile, and amide. Both primary and secondary alkyl
groups can be introduced in good yield, and the reaction
selectivity toward N-alkylation versus O-alkylation was
typically better than 98:2.
Acknowledgment. We thank Dr. Larry Heimark for help
with HRMS analysis.
Finally, prepared 7-PMB-protected derivatives can be
conveniently deprotected to their parent 1- and 1,3-substituted
xanthines either by catalytic hydrogenation (7h to 10, Scheme
2) or under oxidative conditions (9a to 11) using standard
procedures detailed elsewhere.2a,5b,8 The ability to choose
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1, 7a-h, 9a-h,
10, and 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) (a) Singh, S. B. Tetrahedron Lett. 1995, 36, 12, 2009. (b) Nohara,
F.; Nishii, M.; Ogawa, K.; Isono, K.; Ubukata, M.; Fujii, T.; Itaya, T.; Saito,
T. Tetrahedron Lett. 1987, 28, 12, 1287. (c) Forbes, I. T.; Johnson, C. N.;
Thompson, M. J. Chem. Soc. Perkin Trans. 1 1992, 275.
OL049272N
(9) Izawa, K.; Shiragami, H.; Yamashita, K. U.S. Patent 6 087 497, 2000.
2240
Org. Lett., Vol. 6, No. 13, 2004