Palladium-catalyzed reaction of methyl 5-amino-4-chloro-2- methylthiopyrrolo[2,3-d]-pyrimidine-6-carboxylate with arylboronic acids. Synthesis of 1,3,4,6-tetraazadibenzo[cd,f]-azulene heterocyclic system

Article abstract of DOI:10.1007/s10593-010-0636-5

Densely substituted methyl 5-amino-4-aryl-7-methyl-2-methylthio-7H- pyrrolo[2,3-d]pyrimidine-6-carboxy- lates were synthesized by the palladium-catalyzed cross-coupling reaction of methyl 5-amino-4-chloro-7-methyl- 2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with arylboronic acids using Pd(OAc)₂/dicyclohexyl(2-biphenyl)phosphine/K₃PO ₄ as a catalyst system. Reaction of methyl 5-amino-4-chloro-7-methyl- 2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with 2-formylphenyl- boronic acid led to a novel heterocyclic system - 1,3,4,6-tetraazadibenzo[cd,f] azulene.

Full text of DOI:10.1007/s10593-010-0636-5

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
PALLADIUM-CATALYZED REACTION OF METHYL
5-AMINO-4-CHLORO-2-METHYLTHIOPYRROLO[2,3-d]-
PYRIMIDINE-6-CARBOXYLATE WITH ARYLBORONIC
ACIDS. SYNTHESIS OF 1,3,4,6-TETRAAZADIBENZO[cd,f]-
AZULENE HETEROCYCLIC SYSTEM
J. Dodonova1, I. Uogintaite1, V. Masevicius1, and S. Tumkevicius1*
Densely substituted methyl 5-amino-4-aryl-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxy-
lates were synthesized by the palladium-catalyzed cross-coupling reaction of methyl 5-amino-4-chloro-
7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with arylboronic acids using
Pd(OAc)2/dicyclohexyl(2-biphenyl)phosphine/K3PO4 as a catalyst system. Reaction of methyl 5-amino-
4-chloro-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with 2-formylphenyl-
boronic acid led to a novel heterocyclic system – 1,3,4,6-tetraazadibenzo[cd,f]azulene.
Keywords: arylboronic acids, pyrrolo[2,3-d]pyrimidines, 1,3,4,6-tetraazadibenzo[cd,f]azulene, palladium
catalysis, Suzuki–Miyaura reaction.
Arylpurines are of particular importance due to their anti-HCV, cytostatic, and antimycobacterial
activities [1-4]. Arylpyrrolo[2,3-d]pyrimidines as isosters of biogenic purine, are often used as surrogates of
purine bases, and many of them display interesting biological effects [5-11]. For their synthesis, the arylation
reaction is a simple approach that does not involve the preparation of specific intermediates needed in the
synthesis via cyclization procedures. In the past two decades, the Suzuki–Miyaura cross-coupling reaction has
evolved into one of the most widely employed carbon–carbon bond forming processes, including the preparation
of biaryls [12-16]. However, despite the achieved advances in this area some difficulties and limitations still
exist when nitrogen heterocycles are one or both of the coupling partners [17-22]. A literature survey on the
arylpyrrolo[2,3-d]pyrimidines revealed that the Suzuki–Miyaura reaction in a pyrrolo[2,3-d]pyrimi-dine series is
explored insufficiently. To the best of our knowledge, few examples are reported on the application of the
palladium-catalyzed cross-coupling reaction for the arylation of a pyrrole ring of pyrrolo[2,3-d]pyrimidine
[7, 23-27], and only two works have recently been published (one of them is from our laboratory) on the arylation
of a pyrimidine moiety of this heterocycle [28, 29]. In this context and continuing our studies on the synthesis of
pyrimidine derivatives and related heterocycles [30–35], we present herein our results on the palladium-
_______
* To whom correspondence should be addressed, e-mail: sigitas.tumkevicius@chf.vu.lt.
1Vilnius University, Department of Organic Chemistry, Vilnius LT-03225, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1391-1396, September, 2010. Original
article received July 26, 2010.
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0009-3122/10/4609-1122©2010 Springer Science+Business Media, Inc.

catalyzed cross-coupling reaction of the easily obtainable and versatile precursor of polycyclic heterocycles
[31-33] – methyl 5-amino-4-chloro-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (1) with
selected arylboronic acids.
We initially conducted a brief screen of common palladium catalysts and ligands using phenylboronic
acid as the coupling partner of compound 1 in the Suzuki–Miyaura cross-coupling reaction. Performing the
reaction of compound 1 with 1.2 eq. of phenylboronic acid using PdCl2(PPh3)2/K3PO4 as a catalyst system in
anhydrous dioxane at temperatures from ambient to reflux did not give the desired result. Only traces of
compound 2a were detected when the reaction was carried out at the reflux temperature of dioxane for 10 h.
R
R
NH2
B(OH)2
N
COOMe
Pd(0),
ligand,
K3PO4,
N
MeS
N
Cl
NH2
Me
2a–c
dioxane,
N
, argon
9
COOMe
8
10
11
CHO
B(OH)2
N
MeS
N
7
Me
1
N
6
1
N
5
COOMe
MeS
2
N
3
N
4
(MeCO)2O, 
Me
5
R
N
R
Cl
N(COMe)2
COOMe
B(OH)2
N(COMe)2
COOMe
N
Pd(0), ligand,
K3PO4, dioxane,
N
MeS
N
N
MeS
N
Me
, argon
Me
3
4a,b
a R = H, b R = 4-(t-Bu), c R = 3,5-Cl2
Using Pd(OAc)2/PPh3/K3PO4 as a catalyst system furnished the desired 4-phenylpyrrolopyrimidine 2a in
30% yield (Scheme). However, reaction of compound 1 with 4-tert-butylphenylboronic acid under these
conditions gave a complex mixture of products, from which only a negligible amount of compound 2b was
isolated. We supposed that the reason can be an interaction of the primary amino group of compound 1 with
boronic acids or palladium catalyst similar to that observed for 4-amino-2-chloropyrimidine [36]. To clarify the
influence of the 5-amino group of pyrrolo[2,3-d]pyrimidine on the cross-coupling reaction 5-diacetylamino
derivative 3 was synthesized. However, compound 3 did not react with phenyl- or 4-tert-butylphenylboronic
acids to give the desired compounds 4a,b using Pd(OAc)2/PPh3, PdCl2(PPh3)2, or Pd(OAc)2/dicyclohexyl(2-bi-
phenyl)phosphine as catalyst systems and K3PO4 as a base. In all cases the initial compound 3 was recovered.
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Otherwise, the catalytic system, Pd(OAc)2/dicyclohexyl(2-biphenyl)phosphine/K3PO4, appeared to give the best
results in the cross-coupling reaction of compound 1 with arylboronic acids. Compounds 2b,c were obtained in
80 and 64% yields, respectively. Reaction of compound 1 with 2-formylphenylboronic acid under the analogous
conditions furnished a tetracyclic heterocycle, 1,3,4,6-tetraazadibenzo[cd,f]azulene. Structure assignment of
1
compound 5 was based on IR, H, 13C NMR spectral and elemental analysis data. For example, in the IR
spectrum of compound 5 there were no absorption bands for the amino group, which are observed in the IR
spectra of 1 and 2a–c in the region 3269–3453 cm–1. The IR spectrum of compound 5 contains only one CO
absorption band at 1702 cm–1. It is shifted to the region of higher wavenumbers for ca 30 cm–1 in comparison
with that of compounds 1, 2a–c containing the primary amino group capable of forming intramolecular
hydrogen bonds with the adjacent ester group. In the 1H NMR spectrum of compound 5 along with other proton
signals a singlet due to resonance of the CH=N group proton at 8.14 ppm is observed. The 13C NMR spectrum of
compound 5 is also consistent with the proposed structure.
In conclusion, the present investigation provides an access to a densely substituted 4-aryl-
pyrrolo[2,3-d]pyrimidines, which makes these compounds readily available for further chemical and biological
study. The applied approach led to a novel ortho-, peri-fused heterocyclic system, 1,3,4,6-tetraazadibenzo-
[cd,f]azulene containing structural units of pyrimidine, pyrrole, and benzazepine.
EXPERIMENTAL
Melting points were determined in open capillaries using a digital melting point IA9100 series apparatus
(ThermoFischer Scientific) and are uncorrected. IR spectra were obtained on a Perkin–Elmer FT-IR
1
13
spectrophotometer Spectrum BX II in nujol. H and C NMR spectra were recorded on a Varian Unity Inova
spectrometer (300 and 75 MHz, respectively) in CDCl3 using residual CHCl3 signals (7.29 and 77.3 ppm for 1H
13
and C NMR spectra, respectively) as internal standard. Column chromatography was performed using silica
gel 60 (0.040–0.063 mm) (Merck). All reactions and purity of the synthesized compounds were monitored by
TLC using Silica gel 60 F254 aluminum plates (Merck). Visualization was accomplished by UV light.
Arylboronic acids were purchased from Sigma–Aldrich and were used without further purification.
Compound 1 was synthesized according to a procedure described in [32].
Methyl 5-Amino-7-methyl-2-methylthio-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (2a). A
solution of compound 1 (0.1 g, 0.35 mmol) in anhydrous dioxane (25 ml) was flushed with argon, and
phenylboronic acid (46 mg, 0.38 mmol), K3PO4 (0.23 g, 1.08 mmol), 2.5 mol% Pd(OAc)2 (1.9 mg, 0.009 mmol),
and 5 mol% PPh3 (4.7 mg, 0.018 mmol) were added under stirring and argon flow. The reaction mixture was
refluxed under argon for 9 h. Then dioxane was evaporated to dryness. Water was added to the residue, and the
obtained solution was extracted with chloroform. After evaporation of chloroform, the solid was recrystallized
to give 34 mg (30%) of compound 2a as a yellow solid; mp 158°C (dec.) (2-propanol). IR spectrum, , cm–1:
3380, 3367 (NH2), 1670 (CO). 1H NMR spectrum, δ, ppm: 2.69 (3H, s, SCH3); 3.95(3H, s, NCH3); 3.99 (3H, s,
13
COOCH3); 5.11 (2H, s, NH2); 7.55-7.60 (3H, m, H Ph); 7.77-7.79 (2H, m, H Ph). C NMR spectrum, δ, ppm:
14.60; 30.99; 51.37; 103.69; 107.30; 129.05; 129.12; 130.45; 136.54; 137.80; 151.60; 162.13; 163.63; 169.11.
Found, %: C 58.33; H 5.02; N 17.21. C16H16N4O2S. Calculated, %: C 58.52; H 4.91; N 17.06.
Methyl 5-Amino-4-(4-tert-butylphenyl)-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carb-
oxylate (2b). A solution of compound 1 (0.15 g, 0.52 mmol) in anhydrous dioxane (5 ml) was flushed with
argon, and 4-tert-butylphenylboronic acid (121 mg, 0.68 mmol), 2 mol% Pd(OAc)2 (2.2 mg, 0.01 mmol),
4 mol% dicyclohexyl-(2-biphenyl)phosphine (7.4 mg, 0.021 mmol), and K3PO4 (0.29 g, 1.37 mmol) were added
under stirring and argon flow. The reaction mixture was refluxed under argon for 5 h. Then the dioxane was
evaporated to dryness and water was added to the residue. The obtained solution was extracted with benzene,
1124

and the organic layer dried with Na2SO4, filtered, and the solvents evaporated to dryness. The obtained solid was
purified by column chromatography (eluent – benzene) to give 0.16 g (80%) of compound 2b as yellow solid; mp
153-155°C. IR spectrum, , cm–1: 3453, 3350 (NH2), 1667 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 1.40 (9H, s,
t-Bu); 2.69 (3H, s, SCH3); 3.96 (3H, s, NCH3); 3.99 (3H, s, OCH3); 5.29 (2H, br. s, NH2); 7.60 (2H, d, J = 8.1,
H Ph); 7.76 (2H, d, J = 8.1, H Ph). 13C NMR spectrum, δ, ppm: 14.6; 31.1; 31.5; 35.2; 51.4; 103.5; 107.3;
125.4; 126.2; 129.0; 136.8; 151.3; 154.2; 161.8; 163.6; 168.6. Found, %: C 62.66; H 6.39; N 14.51.
C20H24N4O2S. Calculated, %: C 62.48; H 6.29; N 14.57.
Methyl 5-Amino-4-(3,5-dichlorophenyl)-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carb-
oxylate (2c). A solution of compound 1 (0.1 g, 0.35 mmol) in anhydrous dioxane (5 ml) was flushed with argon,
and 3,5-dichlorophenylboronic acid (87 mg, 0.46 mmol), 2 mol% Pd(OAc)2 (1.6 mg, 0.007 mmol), 4 mol%
dicyclohexyl-(2-biphenyl)phosphine (4.9 mg, 0.014 mmol), and K3PO4 (0.19 g, 0.9 mmol) were added. The
reaction mixture was refluxed under argon for 3 h. Then the dioxane was evaporated to dryness and water was
added to a residue. The obtained solution was extracted with benzene, the organic layer dried with Na2SO4 and
filtered, and the filtrate concentrated to 1/3 of the initial volume. The solution was filtered through a layer of
silica gel, and the silica gel was washed once with benzene. After the evaporation of solvents the residue was
recrystallized to give 89.1 mg (64%) of compound 2c as a yellow solid; mp 202–204°C (2-propanol). IR
1
spectrum, , cm–1: 3377, 3269 (NH2), 1679 (CO). H NMR spectrum, δ, ppm (J, Hz): 2.69 (3H, s, SCH3); 3.97
(3H, s, NCH3); 4.00 (3H, s, OCH3); 4.77 (2H, br. s, NH2); 7.56-7.57 (1H, dd, J = 1.8, J = 2.1, H Ph); 7.70-7.71
(2H, dd, J = 1.8, J = 2.1, H Ph). 13C MR spectrum, δ, ppm: 14.6; 31.1; 51.6; 103.5; 108.1; 127.7; 130.5; 135.6;
135.8; 140.3; 151.4; 158.8; 163.5; 169.0. Found, %: C 48.63; H 3.50; N 14.32. C16H14Cl2N4O2S. Calculated, %:
C 48.37; H 3.55; N 14.10.
Methyl 4-Chloro-5-diacetylamino-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carb-
oxylate (3). A mixture of compound 1 (1.0 g, 3.5 mmol) and acetic anhydride (20 ml) was refluxed for 3.5 h.
The acetic anhydride was removed under reduced pressure and the remaining solid recrystallized to give 0.82 g
1
(63%) of compound 3; mp 125.5-127C (2-propanol). IR spectrum, , cm–1: 1720, 1708 (CO). H NMR
spectrum, δ, ppm: 2.34 (6H, s, 2COCH3); 2.64 (3H, s, SCH3); 3.91 (3H, s, NCH3); 4.10 (3H, s, OCH3). Found,
%: C 45.73; H 4.05; N 15.15. C14H15ClN4O4S. Calculated, %: C 45.35; H 4.08; N 15.11.
Methyl 4-Methyl-2-methylthio-4H-1,3,4,6-tetraazadibenzo[cd,f]azulene-5-carboxylate (5) was
synthesized from compound 1 and 2-formylphenylboronic acid according to the procedure described for
1
compound 2c. The reaction time was 2 h. The yield 88%; mp 199–201°C. IR spectrum, , cm–1: 1702 (CO). H
NMR spectrum, δ, ppm: 2.70 (3H, s, SCH3); 4.06 (3H, s, NCH3); 4.07 (3H, s, COOCH3); 7.60–7.65 (3H, m, H Ph);
13
8.14 (1H, s, CH); 8.88–8.91 (1H, m, H Ph). C NMR spectrum, δ, ppm: 14.7; 31.4; 52.7; 109.6; 120.7; 128.6;
129.0; 132.8; 133.1; 135.1; 136.0; 138.1; 151.7; 157.6; 160.0; 162.2; 169.8. Found, %: C 60.22; H 3.98; N 16.39.
C17H14N4O2S. Calculated, %: C 60.34; H 4.17; N 16.56.
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