Divergent synthesis of novel 9-deazaxanthine derivatives via late-stage cross-coupling reactions

Article abstract of DOI:10.1039/c2ob26516h

A small library of 8-substituted 9-deazaxanthines has been prepared by late-stage diversification of an 8-bromo-9-deazaxanthine. By utilizing palladium-catalyzed cross-coupling reactions a single key precursor can be transformed into a variety of 8-substituted-9-deazaxanthine compounds. Three key 8-bromo-9-deazaxanthine intermediates were efficiently prepared from commercially available 6-chlorouracil in six steps.

Full text of DOI:10.1039/c2ob26516h

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PAPER
Divergent synthesis of novel 9-deazaxanthine derivatives via late-stage
cross-coupling reactions†
Francesca Bartoccini,a Giovanni Piersanti,*a Marco Mor,b Giorgio Tarzia,a Patrizia Minetti*c and
Walter Cabric
Received 1st August 2012, Accepted 20th September 2012
DOI: 10.1039/c2ob26516h
A small library of 8-substituted 9-deazaxanthines has been prepared by late-stage diversification of an
8-bromo-9-deazaxanthine. By utilizing palladium-catalyzed cross-coupling reactions a single key
precursor can be transformed into a variety of 8-substituted-9-deazaxanthine compounds. Three key
8-bromo-9-deazaxanthine intermediates were efficiently prepared from commercially available
6-chlorouracil in six steps.
intermediate followed by reductive ring closure to give N7–H
Introduction
9-deazaxanthine with neat triethyl phosphite at high tempera-
ture,7a formic acid and sodium dithionite,7b,c or SnCl2 in the
In light of their occurrence in a wide range of biologically active
presence of DMF.7d However, all these methods are limited by
molecules, pharmaceuticals, and natural products, xanthines
have triggered increasing attention in both the synthetic and
medicinal chemistry communities.1 The xanthine subunit is not
only essential for its bioactivity but is also a privileged pharma-
cophore in drug discovery.2 Particularly, pyrrolo[3,2-d]pyrimi-
dine derivatives (9-deazaxanthine or pyrimidinedione
derivatives) have been shown to have good antagonistic poten-
cies and selectivity profiles for human adenosine receptors,3
whereas some others have antiviral activity or are enzyme inhibi-
tors.4 Consequently, efficient and selective methods to access
this class of compounds are highly valuable.
their low cyclization reaction yields (11–65%), harsh reaction
conditions, and limited selectivities and functional group toler-
ance. Moreover, they have disadvantages in terms of flexibility
and generality. In fact, they are limited to 8-aryl- or 8-styryl-
9-deazaxanthine derivatives, which limit the synthetic diversity
required in modern drug discovery. Because of the limited sub-
strate scope of the methods outlined above, a novel procedure for
the late-stage functionalization of deazaxanthines that would
constitute a new approach to 8-substituted-9-deazaxanthines was
sought.
As part of an ongoing project aimed at the synthesis and bio-
logical evaluation of adenosine receptor antagonists,5 we desired
a procedure that would provide 8-substituted-9-deazaxanthines
(1,3-dialkyl-6-substituted-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
diones) directly from the parent functionalized 9-deazaxanthines,
thereby avoiding commonly employed fragment-based
approaches to 9-deazaxanthines6,7 that typically rely on the step-
wise construction of the 5-nitro-1,3-dialkyl-6-styryluracil
Palladium-catalyzed C–C bond-forming methods are widely
recognized as convenient and efficient means of introducing
aryl, alkenyl, alkynyl, and, more recently, alkyl groups.8 Com-
pared to conventional noncatalytic organic synthesis, these ver-
satile coupling reactions allow the use of easily available
substrates for synthesizing structurally diverse molecules. These
state of the art methods have been implemented in the industrial
manufacturing of pharmaceuticals, advanced materials, and fine
chemicals in the last decade.9 The use of a palladium-catalyzed
cross-coupling reaction is also an effective approach for the rapid
introduction of chemical diversity into a system, since the number
of steps requiring independent optimization is greatly reduced.
With the aim of creating new synthetic strategies to efficiently
gain access to 8-substituted-9-deazaxanthines, we envisioned the
use of a short route to prepare reactive precursors to which a
diverse range of palladium-catalyzed cross-coupling reactions
could be applied.
aDepartment of Biomolecular Sciences, University of Urbino, Piazza
Rinascimento 6, 61029 Urbino (PU), Italy.
E-mail: giovanni.piersanti@uniurb.it; Fax: +390722303313;
Tel: +390722303320
bDipartimento Farmaceutico, Università degli Studi di Parma,
Viale G.P. Usberti 27 A, I-43124 Parma, Italy.
Fax: +390521905006, +390521905007
cChemistry & Analytical Development Department, Sigma-Tau, Via
Pontina Km 30, 400, 00040 Pomezia, Roma, Italy.
E-mail: patrizia.minetti@sigma-tau.it; Fax: +390691393638;
Tel: +390691393906
Our retrosynthetic analysis (Scheme 1) focused on the 9-de-
azaxanthine substructure rather than on a single synthetic target,
with the ultimate goal of establishing a systematically varied
library of derivatives. Step economy arises in this strategy
†Electronic supplementary information (ESI) available: 1H NMR
and 13C NMR spectra of the products obtained. See DOI:
10.1039/c2ob26516h
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transformation of these compounds to pyrimidine-fused ring
systems has been described so far.
Results and discussion
We decided to test our hypothesis and study the incorporation of
the acetic acid side chain via malonate chemistry on 6-chloro-
1,3-dimethyl-5-nitrouracil,11 which can be accessed by nitration
of inexpensive and commercially available 6-chloro-1,3-
dimethyluracil (3a). The N1,N3-substituted 6-chlorouracil com-
pounds (2, 3b) are easily accessible from 1, thus opening up
pathways to the synthesis of a wide range of substituted hetero-
cyclic lactams (Scheme 2).12
Scheme 1 Retrosynthetic analysis.
In an attempt to minimize reaction optimization and chromato-
graphic purification steps, we first developed the one-pot syn-
thesis of the key advanced lactams 6a,b by a conjugate
substitution reaction with malonate, reduction of the nitro group
followed by intramolecular cyclization and facile decarboxyla-
tion of the redundant carboxyl group. Significantly, all the steps
proceeded in good yield, and reaction co-products could be
removed without column chromatography. Multigram amounts
of 6a,b13 were generated rapidly in a sequence carried out in a
single reaction vessel. Additionally, by an appropriate choice of
the alkylating agent, aldehyde, or ketone in the reductive alkyl-
ation of 7a,b, this route is a versatile process for the synthesis of
deazaxanthines with a diverse range of N7-substituents. Direct
conversion of lactams 6a,b to 8-bromodeazaxanthines 7a,b was
carried out by treatment with POBr3 (3 equiv.) for a short reac-
tion time (1 h) to avoid additional C9 bromination and competi-
tive N-dealkylation. Finally, treatment of 7a,b with alkyl iodide
in DMF in the presence of K2CO3 gave the N7-alkylated deriva-
tives 8a–c in good yield. Notably, direct bromination of unsub-
stituted deazaxanthine14 took place exclusively in the beta
position of the pyrrole ring (behavior similar to indole), provid-
ing C9 bromination as reported elsewhere.15 Overall, the process
was safe, reproducible, reliable, robust, and high yielding.
through the development of a single synthetic route to an
advanced intermediate that, on late-stage differential diversifica-
tion, would provide access to the greatest number of targets in
short parallel sequences. The late-stage intermediates 8a–c serve
this function, and they allow for the differential modification of
key nitrogen atoms (N1, N3, and N7) that would enable access
to the majority of known 9-deazaxanthines and unexplored ana-
logues. We anticipated that the densely substituted pyrrolo[3,2-d]-
pyrimidines 8a–c could be assembled by using sequential de-
hydroxy-bromination and nitrogen alkylation and that the key
fused-lactam intermediates 6a,b could be obtained by a one-pot
nitro reduction, amidation, and subsequent decarboxylation of
5a,b (decarboxylative cyclization). The key feature of this new
approach is the regio- and chemoselective C–C bond formation
with a relevant two-carbon nucleophile to provide a suitable and
easily accessible functionalized electrophilic uracil derivative
(4a,b).
Although some arylations of uracil derivatives have been
reported in recent years,10 the development of a practical method
for the proposed strategies, which are initiated by a Michael
substitution, remains
a challenge. Moreover, no further
Scheme 2 Synthesis of late-stage intermediates 8a–c.
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Scheme 3 Palladium-catalyzed cross-coupling reactions of late-stage intermediate 8a.
Isolation of final products was very convenient, and the purity
and impurity profiles were strictly controlled and reproducible.
With this practical synthesis of 8a–c in hand, we then tested
the reactivity of 8a in order to assess the range of 8-substituted-
9-deazaxanthines that could be produced (Scheme 3). In parti-
cular, 8-phenyl- and 8-vinyl-9-deazaxanthines (9a,b) were pre-
pared in good to excellent yields by palladium-catalyzed
reactions of 8a with commercially available boronic acid or
boronic ester (Suzuki coupling).16 Similarly, 8-alkynyl derivative
9c was synthesized in good yield starting from 8a and phenyl-
acetylene following Sonogashira’s protocol. A coupling reaction
between trimethylsilylacetylene and 8a was also performed. The
resulting 8-(trimethylsilyl)ethynyl-9-deazaxanthine (9d) was
obtained in moderate yield. The TMS group could be depro-
tected under basic conditions to give a terminal arylalkyne that
can be used for a second palladium-catalyzed Sonogashira reac-
tion with an aryl halide for the synthesis of unsymmetrical
diarylalkynes.17 In addition, we explored palladium-catalyzed
cyanation because the nitrile group serves as an intermediate for
multiple transformations into other important functional groups
and a series of catalytic methods to convert C–CN bonds into
C–Si, C–H, and C–B bonds in the presence of a rhodium catalyst
has been developed recently.18 The reaction performed with zinc
cyanide and catalytic amounts of Pd2(dba)3, dppf, and Zn in
dimethylacetamide at 120 °C for 3 h afforded the aromatic nitrile
(9e) in good yield. Among the 8-substituted-9-deazaxanthines,
those containing the styryl moiety are the most interesting and
are used in pharmaceutical chemistry. Next, we tried to accom-
plish the synthesis of these compounds via the Heck–Mizoroki
cross-coupling reaction, one of the most powerful and versatile
cross-coupling reactions used to date. The coupling of aryl
halides with alkenes has been used in the synthesis of several
industrially applicable compounds along with a number of
natural products. After reaction condition optimization, we found
that Jeffery conditions gave rise to the desired disubstituted
alkene (9f) in good yield and stereoselectivity. However,
whereas the reaction between 8a and styrene gave the corres-
ponding product in good yield, the electron-deficient olefin
methyl acrylate reacted with 8a to give the regioselectively
coupled product (9g) in only 23% yield. Longer reaction times
or different conditions afforded a side product resulting from a
dehalogenation process. This result is probably related to the low
nucleophilicity of this alkene with respect to styrene and the
difficulty of insertion of the substrate carbon–carbon double
bond into the metal–carbon bond.19 Furthermore, we examined
other olefin arylation conditions using a secondary allylic
alcohol as the alkylating agent. A regioselective Heck coupling
reaction between aryl bromide 8a and but-3-en-2-ol led to the
generation of an arylated allylic alcohol that isomerized in situ to
give β-aryl ketone 9h.20 Ketone 9h was obtained regioselectively
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in moderate yield by the treatment of 8a with but-3-en-2-ol in
the presence of Pd(OAc)2, LiCl and triethylamine in DMF at
120 °C for 72 h. This reaction is quite remarkable because
highly functionalized carbonyl compounds can be readily trans-
formed to numerous valuable synthons. In addition, it represents
the first “formal” example of introducing a functionalized alkyl
group. The favorable results obtained so far prompted us to
explore the more challenging cross-coupling of C(sp3) organo-
metallic compounds. Based on our previous palladium-catalyzed
direct alkylation of 2-halopurines21 with triethyl- or tri-n-butyl-
borane, we applied a B-alkyl Suzuki–Miyaura cross-coupling
reaction in the presence of Cs2CO3 and catalytic amounts of
Pd(dppf)Cl2·CH2Cl2 in THF with 8a to afford 8-n-butyl-9-de-
azaxanthine (9i) in acceptable yield. A small comparative study
with other organometallics revealed that, with the exception of
tetra-n-butyltin, no other organometallics, including n-butylzinc
chloride, were able to produce the alkylated product.
molecular ions (M + 1 or M − 1) are given. IR spectra were
obtained on a Nicolet Avatar 360 FT-IR spectrometer, absor-
bance values are reported in cm−1. Melting points were deter-
mined on a Buchi SMP-510 capillary melting point apparatus
and are uncorrected. Elemental analyses were performed on a
Carlo Erba analyzer and the results are within 0.3 of the theo-
retical values (C,H,N).
6-Chlorouracil (1) and 6-chloro-1,3-dimethyluracil (3a) are
commercially available.
General procedure for alkylation of 6-chlorouracil derivatives
To a solution of the appropriate 6-chlorouracil derivatives (1 or
2) (1 equiv.) in dry DMF (2.5 ml × mmol) was added NaH (60%
dispersion in mineral oil) (2.2 equiv.). The mixture was stirred
for 50 min, then was added diethyl sulfate. The mixture was
stirred at 60 °C for 24 h, cooled at room temperature, diluted
with water (5 ml × mmol) and extracted with CH2Cl2 (3 × (7 ml
× mmol)). The combined organic phases were dried over anhy-
drous Na2SO4, the solvent was evaporated under reduced
pressure and the residue obtained was purified by flash
chromatography.
Conclusions
In conclusion, we were able to access compounds 8a–c
(Scheme 2) as key late-stage intermediates that could be rapidly
diversified en route to 8-substituted-9-deazaxanthines, an inter-
esting scaffold that exhibits a remarkable range of potent biologi-
cal activities, in a practical step-economical sequence. The key
steps in the synthesis are a selective C–C bond formation by con-
jugate substitution of malonate on reactive 6-chloro-1,3-
dimethyl-5-nitrouracil and a zinc-mediated reductive cyclization
to form the adjacent fused, five-membered ring. The practical
benefits include readily available and inexpensive starting
materials, substrate versatility, experimentally straightforward
procedures, and good product yields. The utility of 8a was
demonstrated by the rapid preparation of six categorically dis-
tinct analogues of 9-deazaxanthine. The synthesis of these com-
pounds (9a–i) was enabled by a late-stage diversification strategy
relying on palladium-catalyzed methodology. But, in some
cases, the yields for the palladium-catalyzed cross-coupling reac-
tion were attenuated due to the reason discussed above. Nonethe-
less, this strategy allowed the rapid diversification of 8a to
evaluate the effects of sterically and electronically differentiated
groups in this position of the pyrrole ring to investigate struc-
ture–activity relationships. Facile access to these structures is
desirable in a medicinal chemistry22 program because it enables
the rapid generation of diversity around a basic structure.
6-Chloro-1-ethylpyrimidine-2,4(1H,3H)-dione (2).23 The
general procedure was followed using 6-chloro-uracil (1) (1 g,
6.8 mmol) and diethyl sulfate (5.3 ml, 41 mmol). The residue
was purified by flash chromatography (gradient from cyclo-
hexane–ethyl acetate 8 : 2 to cyclohexane–ethyl acetate 1 : 1) to
give 2 (735 mg, 62%). White solid, mp: 193–195 °C (methanol);
1H NMR (200 MHz, CDCl3) δ 9.85 (bs, 1H), 5.90 (s, 1H), 4.18
(q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); IR (nujol, cm−1):
1682, 1647; MS (ESI) (m/z): 175 [M + H]+; Anal. Calcd for
C6H7ClN2O2 (174.02): C, 41.28; H, 4.04; N, 16.05. Found: C,
41.36; H, 3.98; N, 16.11.
6-Chloro-1,3-diethylpyrimidine-2,4(1H,3H)-dione (3b).24 The
general procedure was followed using 6-chloro-1-ethyluracil (2)
(950 mg, 5.5 mmol) and diethyl sulfate (1.6 ml, 12 mmol). The
residue was purified by flash chromatography (cyclohexane–
ethyl acetate 1 : 1) to give 3b (810 mg, 73%). White solid, mp:
1
121–123 °C (methanol); H NMR (200 MHz, CDCl3) δ 5.89 (s,
1H), 4.13 (q, J = 7.0 Hz, 2H), 3.97 (q, J = 7.0 Hz, 2H), 1.31 (t,
J = 7.0 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 12.7, 13.9, 36.9, 42.4, 102.1, 145.4, 150.4, 160.6; IR
(nujol, cm−1): 1682, 1647; MS (ESI) (m/z): 203 [M + H]+; Anal.
Calcd for C8H11ClN2O2 (202.05): C, 47.42; H, 5.47; N, 13.82.
Found: C, 47.38; H, 5.51; N, 13.88.
Experimental section
All reactions were run in air unless otherwise noted. Column
chromatography purifications were performed in flash conditions
using Merck 230–400 mesh silica gel. Analytical thin layer
chromatography (TLC) was carried out on Merck silica gel
plates (silica gel 60 F254), that were visualized by exposure to
General procedure for nitration, substitution with diethyl
malonate, reduction, amidation and subsequent decarboxylation
of 6-chloro-1,3-dialkyluracil
(a) To concentrated sulphuric acid (0.5 ml × mmol), at 0 °C, the
appropriate 6-chloro-1,3-dialkyluracil (3a or 3b) (1 equiv.) was
added portionwise. The mixture was stirred at 0 °C for 2 min,
then was slowly added fuming nitric acid (0.16 ml × mmol). The
solution was stirred at this temperature for 30 min, then poured
onto ice, diluted with water (4 ml × mmol) and extracted with
CH2Cl2 (3 × (6 ml × mmol)). The combined organic phases
1
ultraviolet light. H NMR and 13C NMR spectra were recorded
on a Bruker Avance 200 spectrometer, using CDCl3 or DMSO-
d6 as a solvent. Chemical shifts (δ scale) are reported in parts per
million (ppm) relative to the central peak of the solvent. Coup-
ling constants (J values) are given in Hertz (Hz). ESI-MS spectra
were taken on a Waters Micromass ZQ instrument, only
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were dried over anhydrous Na2SO4 and the solvent was evapor-
ated under reduced pressure to give 6-chloro-5-nitro-1,3-dialkyl-
uracil (4a24 or 4b). (Note: The aqueous solution must be
extracted immediately otherwise you have degradation of
product.)
(b) To a solution of diethyl malonate (1.2 equiv.) in anhydrous
dioxane (2.4 ml × mmol), under N2, was added potassium t-but-
oxide (2 equiv.). The mixture was stirred for 10 min, then was
added a solution of the appropriate 6-chloro-5-nitro-1,3-dialkyl-
uracil (4a or 4b) (1 equiv.) in dioxane (1.2 ml × mmol). The
mixture was stirred at room temperature for 1 h, then was added
anhydrous HCl 4 M in dioxane (2 equiv.) (the colour of the solu-
tion changed from orange to yellowish). The solvent was evapor-
ated under reduced pressure to give diethyl 2-(1,3-dialkyl-5-
nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)malonate (5a or
5b).
(c) To a solution of the appropriate malonate derivatives 5a or
5b (1 equiv.) in acetic acid (3.5 ml × mmol), at 60 °C, zinc
powder (15 equiv.) was added portionwise. The mixture was
stirred at 120 °C for 4 h, then filtered through a pad of Celite
keeping the solution hot and washed with hot acetic acid (2 ×
(3 ml × mmol)) and hot methanol (2 × (3 ml × mmol)). The sol-
vents were evaporated under reduced pressure and the residue
obtained was purified by flash chromatography.
then poured on a saturated solution of NaHCO3 (12 ml × mmol)
and ethyl acetate (12 ml × mmol). The phases were separated
and the aqueous phase was extracted with further ethyl acetate
(8 × (7 ml × mmol)). The combined organic phases were dried
over anhydrous Na2SO4, the solvent was evaporated under
reduced pressure and the residue obtained was used for the
following reaction without further purification.
6-Bromo-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (7a). The general procedure was followed using
6-hydroxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (6a) (1.6 g, 8.2 mmol) to give 7a (1.93 g, 92%). An
analytical sample was purified by flash chromatography
(CH2Cl2–MeOH 94 : 6) for the characterization. Off-white solid,
mp: >220 °C (methanol); 1H NMR (200 MHz, DMSO-d6):
δ 12.95 (bs, 1H), 6.39 (d, J = 2.0 Hz, 1H), 3.34 (s, 3H), 3.22 (s,
3H); 13C NMR (50 MHz, DMSO-d6): δ 28.0, 32.4, 98.35, 110.8,
111.5, 136.1, 151.3, 154.2; IR (nujol, cm−1): 3125, 1701, 1647;
MS (ESI) (m/z): 258–260 [M + H]+ and 256–258 [M − H]−;
Anal. Calcd for C8H8BrN3O2 (256.98): C, 37.23; H, 3.12; N,
16.28. Found: C, 37.31; H, 3.16; N, 16.21.
6-Bromo-1,3-diethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (7b). The general procedure was followed using 6-
hydroxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (6b) (495 mg, 2.2 mmol) to give 7b (565 mg, 90%). An
analytical sample was purified by flash chromatography
(CH2Cl2–MeOH 94 : 6) for the characterization. Off-white solid,
mp: >220 °C (methanol); 1H NMR (200 MHz, DMSO-d6):
δ 12.89 (bs, 1H), 6.40 (d, J = 2.0 Hz, 1H), 3.90 (q, J = 7.0 Hz,
2H), 3.87 (q, J = 7.0 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H), 1.11 (t,
J = 7.0 Hz, 3H); 13C NMR (50 MHz, DMSO-d6): δ 13.2, 13.7,
35.9, 39.8, 98.1, 111.0, 111.8, 135.1, 150.3, 153.8; IR (nujol,
cm−1): 3120, 1696, 1660; MS (ESI) (m/z): 286–288 [M + H]+
and 284–282 [M − H]−; Anal. Calcd for C10H12BrN3O2
(285.01): C, 41.98; H, 4.23; N, 14.69. Found: C, 42.06; H, 4.18;
N, 14.78.
6-Hydroxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (6a). The general procedure was followed using 6-chloro-
1,3-dimethyluracil (3a) (3 g, 17.2 mmol). The residue was
purified by flash chromatography (gradient from CH2Cl2–MeOH
99 : 1 to CH2Cl2–MeOH 94 : 6) to give 6a (1.62 g). Overall
yield from 3a: 48%. Yellowish solid, mp: >260 °C (methanol);
1H NMR (200 MHz, DMSO-d6): δ 11.41 (bs, 1H), 5.18 (d, J =
2.0 Hz, 1H), 3.38 (bs, 1H), 3.29 (s, 3H), 3.18 (s, 3H); 13C NMR
(50 MHz, DMSO-d6): δ 27.7, 32.1, 76. 3, 100.7, 115.6, 137.1,
151.7, 153.6; IR (nujol, cm−1): 3350, 3120, 1701, 1647; MS
(ESI) (m/z): 196 [M + H]+ and 194 [M − H]−; Anal. Calcd for
C8H9N3O3 (195.06): C, 49.23; H, 4.65; N, 21.53. Found: C,
49.12; H, 4.59; N, 21.58.
General procedure for N7 alkylation
1,3-Diethyl-6-hydroxy-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (6b). The general procedure was followed using 6-chloro-
1,3-diethyluracil (3b) (1 g, 4.9 mmol). The residue was purified
by flash chromatography (gradient from CH2Cl2–MeOH 99 : 1
to CH2Cl2–MeOH 94 : 6) to give 6b (495 mg). Overall yield
from 3b: 45%. Yellowish solid, mp: >260 °C; 1H NMR
(200 MHz, DMSO-d6): δ 11.34 (bs, 1H), 11.23 (bs, 1H), 5.18
(d, J = 2.0 Hz, 1H), 3.92–3.75 (m, 4H), 1.15 (t, J = 7.0 Hz, 3H),
1.08 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz, DMSO-d6): δ
13.1, 13.7, 35.2, 39.5, 75.9, 101.1, 136.1, 150.4, 152.9, 153.5;
IR (nujol, cm−1): 3352, 3118, 1703, 1653; MS (ESI) (m/z): 224
[M + H]+ and 222 [M − H]−; Anal. Calcd for C10H13N3O3
(223.10): C, 53.80; H, 5.87; N, 18.82. Found: C, 53.75; H, 5.83;
N, 18.96.
To a solution of the appropriate brominated derivatives 7a or 7b
(1 equiv.) in dry DMF (7.5 ml × mmol) were added K2CO3 (1.1
equiv.) and alkyl iodide (10 equiv.). The mixture was stirred at
45 °C for 1 h, cooled at room temperature, diluted with water
(4 ml × mmol) and extracted with CH2Cl2 (3 × (4 ml × mmol)).
The combined organic phases were dried over anhydrous
Na2SO4, the solvent was evaporated under reduced pressure and
the residue obtained was purified by flash chromatography.
6-Bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (8a). The general procedure was followed using 7a (1.9 g,
7.4 mmol) and methyl iodide (4.6 ml, 74 mmol). The residue
obtained was purified by flash chromatography (CH2Cl2–MeOH
96 : 4) to obtain 8a (1.5 g, 74%). White solid, mp: 207–209 °C
1
(ethanol); H NMR (200 MHz, CDCl3): δ 6.04 (s, 1H), 4.00 (s,
3H), 3.44 (s, 3H), 3.41 (s, 3H); 13C NMR (50 MHz, CDCl3):
δ 27.8, 31.7, 33.9, 96.8, 111.2, 115.7, 135.6, 151.3, 155.1; IR
(nujol, cm−1): 1701, 1647; MS (ESI) (m/z): 274–272 [M + H]+;
Anal. Calcd for C9H10BrN3O2 (271.00): C, 39.73; H, 3.70; N,
15.44. Found: C, 39.84; H, 3.65; N, 15.51.
General procedure for the dehydroxy-bromination
To a solution of the appropriate lactam derivatives 6a or 6b
(1 equiv.) in dioxane (10 ml × mmol) was added POBr3
(3 equiv.). The mixture was stirred at 100 °C for 1 h, cooled and
8864 | Org. Biomol. Chem., 2012, 10, 8860–8867
This journal is © The Royal Society of Chemistry 2012

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6-Bromo-1,3-diethyl-5-methyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-
(3H,5H)-dione (8b). The general procedure was followed using
7b (565 mg, 2.0 mmol) and methyl iodide (1.2 ml, 20 mmol).
The residue obtained was purified by flash chromatography
(CH2Cl2–MeOH 96 : 4) to obtain 8b (390 mg, 65%). White
31.7, 90.7, 110.8, 118.6, 123.8, 135.4, 140.0, 151.5, 156.0; IR
(nujol, cm−1): 2924, 1684, 1646; MS (ESI) (m/z): 220 [M + H]+;
Anal. Calcd for C11H13N3O2 (219.10): C, 60.26; H, 5.98; N,
19.17. Found: C, 60.36; H, 5.91; N, 19.26.
1
1,3,5-Trimethyl-6-(phenylethynyl)-1H-pyrrolo[3,2-d]pyrimidine-
2,4(3H,5H)-dione (9c). A flame-dried Schlenk tube was
charged with 6-bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimi-
dine-2,4(3H,5H)-dione (8a) (108 mg, 0.4 mmol), Pd(PPh3)2Cl2
(14 mg, 0.02 mmol), CuI (8 mg, 0.04 mmol), dioxane (1.6 ml)
and TEA (84 μL, 0.6 mmol), under N2. Phenylacetylene (48 μl,
0.44 mmol) was then added and the resulting black reaction
mixture was stirred at 100 °C for 20 h. The mixture was diluted
with CH2Cl2 (3 ml), filtered through a pad of Celite and washed
with CH2Cl2 (3 × 10 ml). The solvent was evaporated under
reduced pressure and the residue obtained was purified by flash
chromatography (CH2Cl2–MeOH 98 : 2) to give 9c (115 mg,
98%). White solid, mp: 186–188 °C (ethanol); 1H NMR
(200 MHz, CDCl3): δ 7.56–7.53 (m, 2H), 7.41–7.38 (m, 3H),
6.18 (s, 1H), 4.10 (s, 3H), 3.46 (s, 3H), 3.42 (s, 3H); 13C NMR
(50 MHz, CDCl3): δ 27.9, 31.7, 33.5, 78.8, 97.1, 98.1, 111.3,
121.7, 123.9, 128.6, 129.3, 131.5, 134.6, 151.5, 155.5; IR
(nujol, cm−1): 2201, 1690, 1653; MS (ESI) (m/z): 294 [M + H]+;
Anal. Calcd for C17H15N3O2 (293.12): C, 69.61; H, 5.15;
N, 14.33. Found: C, 69.72; H, 5.22; N, 14.26.
solid, mp: 196–198 °C (ethanol); H NMR (200 MHz, CDCl3):
δ 6.03 (s, 1H), 4.09 (q, J = 7.0 Hz, 2H), 4.01 (s, 3H), 3.93 (q,
J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz,
3H); 13C NMR (50 MHz, CDCl3): δ 12.8, 13.3, 33.9, 36.3, 40.3,
96.5, 111.6, 115.5, 134.7, 150.4, 154.8; IR (nujol, cm−1): 1705,
1652; MS (ESI) (m/z): 300–302 [M + H]+; Anal. Calcd for
C11H14BrN3O2 (299.03): C, 44.02; H, 4.70; N, 14.00. Found: C,
44.14; H, 4.73; N, 13.96.
6-Bromo-5-ethyl-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-
(3H,5H)-dione (8c). The general procedure was followed using
7a (200 mg, 0.78 mmol) and ethyl iodide (0.6 ml, 7.8 mmol).
The residue obtained was purified by flash chromatography
(CH2Cl2–MeOH 96 : 4) to obtain 8c (110 mg, 49%). White
1
solid, mp: 212–214 °C (ethanol); H NMR (200 MHz, CDCl3):
δ 6.02 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.42 (s, 3H), 3.40 (s,
3H), 1.35 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3):
δ 16.1, 27.9, 31.7, 42.2, 96.9, 110.3, 114.3, 135.8, 151.4, 154.6;
IR (nujol, cm−1): 1705, 1652; MS (ESI) (m/z): 286–288
[M + H]+; Anal. Calcd for C10H12BrN3O2 (285.01): C, 41.98;
H, 4.23; N, 14.69. Found: C, 42.05; H, 4.19; N, 14.76.
1,3,5-Trimethyl-6-((trimethylsilyl)ethynyl)-1H-pyrrolo[3,2-d]-
pyrimidine-2,4(3H,5H)-dione (9d). A flame-dried Schlenk tube
was charged with 6-bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]-
pyrimidine-2,4(3H,5H)-dione (8a) (108 mg, 0.4 mmol), Pd
(PPh3)2Cl2 (14 mg, 0.02 mmol), CuI (8 mg, 0.04 mmol),
dioxane (1.6 ml) and TEA (84 μL, 0.6 mmol), under N2. Tri-
methylsilylacetylene (62 μl, 0.44 mmol) was then added and the
resulting black reaction mixture was stirred at 100 °C for 20 h.
The mixture was diluted with CH2Cl2 (3 ml), filtered through a
pad of Celite and washed with CH2Cl2 (3 × 10 ml). The solvent
was evaporated under reduced pressure and the residue obtained
was purified by flash chromatography (cyclohexane–ethyl
acetate 7 : 3) to give 9d (40 mg, 34%). White solid, mp:
132–134 °C (acetone–hexane); 1H NMR (200 MHz, CDCl3):
δ 6.11 (s, 1H), 4.01 (s, 3H), 3.42 (s, 3H), 3.40 (s, 3H), −0.28 (s,
9H); 13C NMR (50 MHz, CDCl3): δ −0.3, 27.9, 31.7, 33.4,
93.7, 98.4, 103.9, 111.1, 123.7, 134.3, 151.5, 155.5; IR (nujol,
cm−1): 2157, 1697, 1654; MS (ESI) (m/z): 290 [M + H]+; Anal.
Calcd for C14H19N3O2Si (289.12): C, 58.10; H, 6.62; N, 14.52.
Found: C, 58.16; H, 6.69; N, 14.63.
1,3,5-Trimethyl-6-phenyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (9a). A flame-dried Schlenk tube was charged with
6-bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (8a) (108 mg, 0.4 mmol), phenylboronic acid (73.15 mg,
0.6 mmol), powdered K3PO4·H2O (460.6 mg, 2 mmol),
Pd(OAc)2 (9 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,6′-
dimethoxybiphenyl (S-Phos) (33 mg, 0.08 mmol) and toluene
(2 ml), under nitrogen. The mixture was heated at 90 °C for 3 h.
The solvent was evaporated under reduced pressure and the
residue obtained was purified by flash chromatography
(CH2Cl2–MeOH 98 : 2) to give 9a (100 mg, 92%). White solid,
mp: 184–186 °C (ethanol); 1H NMR (200 MHz, CDCl3): δ 7.46
(s, 5H), 5.97 (s, 1H), 3.97 (s, 3H), 3.48 (s, 3H), 3.43 (s, 3H);
13C NMR (50 MHz, CDCl3): δ 27.85, 31.70, 33.63, 94.20,
111.29, 128.76, 128.93, 129.20, 130.66, 135.61, 143.12, 151.65,
156.12; IR (nujol, cm−1): 1691, 1641; MS (ESI) (m/z): 270
[M + H]+; Anal. Calcd for C15H15N3O2 (269.12): C, 66.90;
H, 5.61; N, 15.60. Found: C, 66.98; H, 5.59; N, 15.53.
1,3,5-Trimethyl-6-vinyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (9b). A flame-dried Schlenk tube was charged with
6-bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (8a) (100 mg, 0.37 mmol), 4,4,5,5-tetramethyl-2-vinyl-
1,3,2-dioxaborolane (91 mg, 0.59 mmol), PdCl2(PPh3)2 (26 mg,
0.037 mmol), DME (0.84 ml), H2O (0.16 ml) and TEA (155 μl,
0.59 mmol). The mixture was stirred at 80 °C for 16 h. The
solvent was evaporated under reduced pressure and the residue
obtained was purified by flash chromatography (cyclohexane–
ethyl acetate 7 : 3) to give 9b (54 mg, 67%). Off-white solid,
mp: 216–218 °C (ethanol); 1H NMR (200 MHz, CDCl3): δ 6.68
(dd, J1 = 17.5 and J2 = 11.0 Hz, 1H), 6.09 (s, 1H), 5.82 (d, J =
17.5 Hz, 1H), 5.48 (d, J = 11.0 Hz, 1H), 4.03 (s, 3H), 3.47 (s,
3H), 3.42 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 27.8, 31.6,
1,3,5-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]-
pyrimidine-6-carbonitrile (9e). To a suspension of 6-bromo-
1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (8a)
(136 mg, 0.5 mmol) in dimethylacetamide (0.4 ml) were added
zinc powder (3 mg, 0.048 mmol), diphenylphosphinoferrocene
(10 mg, 0.018 mmol), zinc cyanide (35 mg, 0.3 mmol), and tris-
(dibenzylideneacetone)dipalladium(0) (8 mg, 0.009 mmol)
under nitrogen. The mixture was heated at 120 °C for 3 h and
then was cooled at room temperature. The reaction mixture was
directly transferred onto a column and purified by flash chrom-
atography (CH2Cl2–MeOH 98 : 2) to give 9e (81 mg, 74%).
White solid, mp: 256–258 °C (acetone–hexane); 1H NMR
(200 MHz, CDCl3): δ 6.48 (s, 1H), 4.15 (s, 3H), 3.46 (s, 3H),
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3.41 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 28.1, 31.8, 34.6,
101.8, 111.5, 111.6, 113.9, 133.7, 151.1, 155.5; IR (nujol,
cm−1): 2229, 1688, 1657; MS (ESI) (m/z): 219 [M + H]+; Anal.
Calcd for C10H10N4O2 (218.08): C, 55.04; H, 4.62; N, 25.68.
Found: C, 55.13; H, 4.68; N, 25.79.
was evaporated under reduced pressure and the residue obtained
was purified by flash chromatography (CH2Cl2–MeOH 98 : 2) to
give 9h (47 mg, 45%). White solid, mp: 161–163 °C (acetone–
1
hexane); H NMR (200 MHz, CDCl3): δ 5.68 (s, 1H), 3.96 (s,
3H), 3.43 (s, 3H), 3.40 (s, 3H), 2.90–2.87 (m, 4H), 2.23 (s, 3H);
13C NMR (50 MHz, CDCl3): δ 19.9, 27.7, 30.0, 31.6, 31.7,
41.6, 92.1, 110.1, 135.5, 142.0, 151.6, 155.8, 206.2; IR (nujol,
cm−1): 1713, 1687, 1643; MS (ESI) (m/z): 264 [M + H]+; Anal.
Calcd for C13H17N3O3 (263.13): C, 59.30; H, 6.51; N, 15.96.
Found: C, 59.25; H, 6.46; N, 16.03.
(E)-1,3,5-Trimethyl-6-styryl-1H-pyrrolo[3,2-d]pyrimidine-2,4-
(3H,5H)-dione (9f). A flame-dried Schlenk tube was charged
with potassium acetate (73 mg, 0.74 mmol), tetrabutylammo-
nium bromide (119 mg, 0.37 mmol), powder 3 Å molecular
sieves (74 mg) and dry DMF (0.4 ml), the mixture was stirred
for 15 min. 6-Bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimi-
dine-2,4(3H,5H)-dione (8a) (100 mg, 0.37 mmol) and styrene
(85 μl, 0.74 mmol) were then successively added and the sus-
pension was stirred for another 15 min before addition of
Pd(OAc)2 (4 mg, 0.019 mmol). The mixture was then stirred at
80 °C for 20 h. The mixture was cooled at room temperature,
diluted with CH2Cl2 (3 ml), filtered through a pad of Celite and
washed with CH2Cl2 (3 × 10 ml). The solvent was evaporated
under reduced pressure and the residue obtained was purified by
flash chromatography (CH2Cl2–MeOH 98 : 2) to give 9f (83 mg,
76%). Off-white solid, mp: 142–144 °C (ethanol); 1H NMR
(200 MHz, CDCl3): δ 7.55–7.50 (m, 2H), 7.45–7.36 (m, 3H),
7.16 (d, J = 16.0 Hz, 1H), 7.00 (d, J = 16.0 Hz, 1H), 6.20
(s, 1H), 4.11 (s, 3H), 3.50 (s, 3H), 3.43 (s, 3H); 13C NMR
(50 MHz, CDCl3): δ 27.9, 31.7, 31.8, 90.6, 111.1, 114.7, 126.7,
128.7, 128.9, 133.1, 135.7, 136.2, 140.2, 151.6, 155.8; IR
(nujol, cm−1): 1687, 1651; MS (ESI) (m/z): 296 [M + H]+; Anal.
Calcd for C17H17N3O2 (295.13): C, 69.14; H, 5.80; N, 14.23.
Found: C, 69.31; H, 5.84; N, 14.30. The chemical–physical data
are according to the literature.3f
6-Butyl-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (9i). A flame-dried Schlenk tube was charged with
6-bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-
dione (8a) (108 mg, 0.4 mmol), Cs2CO3 (390 mg, 1.2 mmol),
Pd(dppf)Cl2·CH2Cl2 (20 mg, 0.024 mmol) and freshly distilled
THF (1.0 ml), under an Ar atmosphere. To the stirred suspension
was added tributylborane 1 M solution in THF (1.2 ml, 1.2 mmol)
and the mixture was stirred at 70 °C for 20 h. To the cooled reac-
tion mixture was added 50% aqueous HOAc (0.5 ml) and the
whole was refluxed for 1 h. The cooled solution was basified with
a saturated solution of NaHCO3 and then extracted with dichloro-
methane (3 × 10 ml). The combined organic layer was washed
successively with water and brine, dried over Na2SO4, filtered, and
the solvent evaporated under reduced pressure. The residue was
purified by flash chromatography (cyclohexane–ethyl acetate 8 : 2)
to give 9i (40 mg, 40%). Yellowish solid, mp: 124–126 °C
1
(acetone–hexane); H NMR (200 MHz, CDCl3): δ 5.71 (s, 1H),
3.93 (s, 3H), 3.44 (s, 3H), 3.41 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H),
1.73–1.64 (m, 2H), 1.61–1.35 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H);
13C NMR (50 MHz, CDCl3): δ 13.8, 22.4, 26.0, 27.7, 30.3, 31.5,
31.6, 92.2, 109.9, 135.6, 143.9, 151.7, 155.8; IR (nujol, cm−1):
1686, 1644; Anal. MS (ESI) (m/z): 250 [M + H]+; Calcd for
C13H19N3O2 (249.15): C, 62.63; H, 7.68; N, 16.85. Found: C,
62.56; H, 7.76; N, 16.79.
(E)-Methyl 3-(1,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-
pyrrolo[3,2-d]pyrimidin-6-yl)acrylate
(9g). A
flame-dried
Schlenk tube was charged with 6-bromo-1,3,5-trimethyl-1H-
pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (8a) (120 mg,
0.44 mmol), methyl acrylate (80 μl, 0.88 mmol), triethylamine
(61 μl, 0.88 mmol), powdered K3PO4·H2O (202 mg,
0.88 mmol), Pd(OAc)2 (4 mg, 0.02 mmol), tri(o-tolyl)phosphine
(11 mg, 0.036 mmol) and dry DMF (0.4 ml), under nitrogen.
The mixture was heated at 80 °C for 20 h. The solvent was eva-
porated under reduced pressure and the residue obtained was
purified by flash chromatography (cyclohexane–ethyl acetate
6 : 4) to give 9g (28 mg, 23%). White solid, mp: 135–137 °C
Acknowledgements
We would like to thank Prof. Gilberto Spadoni for useful
discussions.
Notes and references
1
1 For outstanding direct selective functionalization of xanthine, see:
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see: (f) C. E. Müller and K. A. Jacobson, Handb. Exp. Pharmacol.,
2011, 200, 151. For xanthine scaffolds as phosphodiesterase inhibitors,
see: (g) V. Stefanovich, Drug News Perspect., 1989, 2, 82. For xanthine
scaffolds used in the treatment of bronchial asthma and vascular diseases
and as diuretics, psychoanaleptics, and pulmonary and cardiac stimulants,
see: (h) Y. Wang, S. Chackalamannil, Z. Hu, C. D. Boyle, C. M. Lankin,
Y. Xia, R. Xu, T. Asberom, D. Pissarnitski, A. W. Stamford,
W. J. Greenlee, J. Skell, S. Kurowski, S. Vemulapalli, J. Palamanda,
M. Chintala, P. Wu, J. Myers and P. Wang, Bioorg. Med. Chem. Lett.,
(ethanol); H NMR (200 MHz, CDCl3): δ 7.65 (d, J = 16.0 Hz,
1H), 6.43 (d, J = 16.0 Hz, 1H), 6.29 (s, 1H), 4.13 (s, 3H), 3.84
(s, 3H), 3.48 (s, 3H), 3.43 (s, 3H); 13C NMR (50 MHz, CDCl3):
δ 28.1, 29.7, 32.1, 52.2, 93.5, 120.1, 128.5, 130.3, 134.9, 135.9,
154.7, 156.0, 166.6; IR (nujol, cm−1): 1701, 1687, 1643; MS
(ESI) (m/z): 278 [M + H]+; Anal. Calcd for C13H15N3O4
(277.1): C, 56.31; H, 5.45; N, 15.15. Found: C, 56.24; H, 5.51;
N, 15.09.
1,3,5-Trimethyl-6-(3-oxobutyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4-
(3H,5H)-dione (9h). A flame-dried Schlenk tube was charged
with 6-bromo-1,3,5-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-
(3H,5H)-dione (8a) (108 mg, 0.4 mmol), 1-buten-3-ol (104 μl,
1.2 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), LiCl (34 mg,
0.8 mmol), triethylamine (67 μl, 0.48 mmol) and dry DMF
(4 ml). The mixture was stirred at 120 °C for 72 h. The solvent
8866 | Org. Biomol. Chem., 2012, 10, 8860–8867
This journal is © The Royal Society of Chemistry 2012

View Article Online
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