Access to 6-arylpyrrolo[2,3-d]pyrimidines via a palladium-catalyzed direct C-H arylation reaction

Article abstract of DOI:10.1039/c4ra07088g

An efficient method of palladium-catalyzed direct arylation has been developed for the selective functionalization of the C6 position of 2,4-diarylpyrrolo[2,3-d]pyrimidines. Under optimal conditions, various aryl bromides successfully provided a wide rang

Full text of DOI:10.1039/c4ra07088g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Access to 6-arylpyrrolo[2,3-d]pyrimidines via a
palladium-catalyzed direct C–H arylation reaction†
Cite this: RSC Adv., 2014, 4, 35966
*
Jelena Dodonova and Sigitas Tumkevicius
Received 17th June 2014
Accepted 29th July 2014
An efficient method of palladium-catalyzed direct arylation has been developed for the selective
functionalization of the C6 position of 2,4-diarylpyrrolo[2,3-d]pyrimidines. Under optimal conditions,
various aryl bromides successfully provided a wide range of 6-arylpyrrolo[2,3-d]pyrimidines.
DOI: 10.1039/c4ra07088g
www.rsc.org/advances
induced emission enhancement.11 Compounds possessing a
functionalized pyrrolo[2,3-d]pyrimidine scaffold can be
Introduction
prepared by cyclocondensation reactions starting either from
the appropriately substituted pyrrole5b,12 or pyrimidine6c,13
derivatives as common intermediates. However, these strate-
gies oen require multistep syntheses, and thus the synthesis
of polysubstituted pyrrolopyrimidines using such methods
tends to be lengthy. On the other hand, pyrrolo[2,3-d]pyrim-
idine can be functionalized using late-stage functionalization
methods, such as transition metal-catalyzed cross-coupling
reactions. Generally, such methods allow the introduction of
different aryl moieties into various positions of the hetero-
cycle and diversely functionalized pyrrolo[2,3-d]pyrimidines
can be obtained in good yields.3,4,10,13e,14 Despite signicant
advances in cross-coupling reactions, multiple steps are
usually required for installing active groups and none of the
preactivation groups appears in the nal product. Therefore,
in recent years direct arylation reactions that are more atom-
economic and step-simplied have emerged as attractive
alternatives to these more commonly employed cross-
coupling reactions.15 Although direct arylation has been
demonstrated on a wealth of aromatic heterocycles so far,
there remains a multitude of heteroaromatic ring systems
that have not been investigated, including pyrrolo[2,3-d]
pyrimidine. To the best of our knowledge, the only attempt to
synthesize 6-arylpyrrolopyrimidines by direct arylation of
7-benzyl-4-phenylpyrrolo[2,3-d]pyrimidine with iodoarenes
and heteroarenes was made by Hocek and co-workers.14a
However, the reaction gave products (3 examples) in low 35–
41% yields, or did not take place. Because the pyrrolo[2,3-d]
pyrimidine ring system represents an important pharmaco-
phore in drug discovery and its aryl derivatives possess valu-
able photophysical properties, efficient and economic
methods for the synthesis of arylpyrrolo[2,3-d]pyrimidines are
highly desirable. Therefore, we have investigated the direct
arylation of pyrrolopyrimidines to provide easy access to
6-arylpyrrolo[2,3-d]pyrimidines.
Pyrrolo[2,3-d]pyrimidine, and its aryl and heteroaryl deriva-
tives, display a wide range of biological activities, such as
inhibition of protein kinases,1 thymidylate synthase2 and
dihydrofolate reductase,3 antitumor4 and antimicrobial
properties,5 antagonist effects on receptors,6 and cytostatic
and antiproliferative effects.6a,7 Examples of synthetic bio-
logically active compounds possessing a pyrrolo[2,3-d]pyrim-
idine core include EGFR-tyrosine kinases inhibitor AEE-788,8
ACK1 inhibitors4 and GSK-3b inhibitors that induce neuro-
genesis (TWS119)9 (Fig. 1).
In addition to these applications, oligoarylenes with a
pyrrolo[2,3-d]pyrimidine core exhibit strong UV-blue uores-
cence and are promising candidates as uorescent functional
materials.10 Moreover, some pyrrolo[2,3-d]pyrimidine deriva-
tives form uorescent nanoaggregates and show aggregation-
Fig. 1 Biologically active pyrrolo[2,3-d]pyrimidines.
Vilnius University, Department of Organic Chemistry, Naugarduko 24, LT-03225
Vilnius, Lithuania. E-mail: sigitas.tumkevicius@chf.vu.lt
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra07088g
35966 | RSC Adv., 2014, 4, 35966–35974
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
anions in the reaction mixture, and that this catalyst poisoning
can be overcome by adding AgOTf or Ag2CO3 to the reaction
mixture.18 However, in our case, addition of Ag2CO3 was useless
and product 2a was obtained almost in the same yield (Table 1,
entry 7).
Results and discussion
Initially, our efforts were focused on identifying the catalytic
system and reaction conditions for the direct arylation of
compound 1a with 4-iodoanisole (Table 1). We began by ary-
lating pyrrolo[2,3-d]pyrimidine 1a with the catalyst system used
by Hocek and co-workers.14a Aer heating the reaction mixture
at 170 ꢀC for 72 h in the presence of Pd(OAc)2/CuI/Cs2CO3,
product 2a was obtained in a low yield of 21% (Table 1, entry 1).
A slightly higher yield for 2a (34%) was obtained when a catalyst
system composed of Pd(OAc)2, P(2-biPh)Cy2 and K2CO3 was
employed (Table 1, entry 2). These results together with the
previously reported results,14a,16 indicate that the catalyst system
suitable for the direct arylation of purines does not work well in
a pyrrolo[2,3-d]pyrimidine series. Otherwise, conditions similar
to Fagnou and co-workers' direct heteroaryl arylation proce-
dure17 allowed the direct C6 arylation of pyrrolo[2,3-d]pyrimi-
dine 1a to proceed at 170 ꢀC and provided 2a in 80% yield (Table
1, entry 3). Decreasing the loading of the catalyst from 5 to 2
mol% led to a lower yield of compound 2a (40%) (Table 1, entry
4). It is also interesting to note the role of pivalic acid; the
reaction performed without pivalic acid under the same
conditions furnished 2a in only 46% yield (Table 1, entry 5).
Addition of pivalic acid (30 mol%) to the catalyst system
Pd(OAc)2/P(2-biPh)Cy2/K2CO3 also increased the reactivity of 1a,
and product 2a was obtained in 51% yield (Table 1, compare
entry 6 with entry 2).
In order to compare the reactivity of aryl bromides and aryl
iodides, we decided to examine the reaction of pyrrolo[2,3-d]
pyrimidine 1a with 4-bromoanisole using the same catalytic
system, Pd(OAc)2/PCy3$HBF4/PivOH/K2CO3/DMA. Aer 72 h
heating at 170 ꢀC the desired product was obtained in 79%
yield (Table 1, entry 8). However, when free tricyclohexyl-
phosphine was used as a ligand, only traces of target
compound 2a were isolated (Table 1, entry 9). Changing the
reaction solvent from DMA to dioxane resulted in the forma-
tion of compound 2a in only 10% yield (Table 1, entry 10). To
clarify the reactivity of aryl iodides and bromides with elec-
tron-withdrawing groups, C–H arylation using 4-iodo or
4-bromo benzonitrile was carried out. In contrast to 4-iodoa-
nisole, 4-iodobenzonitrile reacted with pyrrolo[2,3-d]pyrimi-
dine 1a very poorly and compound 2b was obtained in only
17% yield (Table 1, entry 11). Moreover, along with the target
C6-arylated product 2b, 5,50-bipyrrolo[2,3-d]pyrimidine 3 was
also isolated.
Meanwhile, 4-bromobenzonitrile under the same reaction
conditions furnished the C6 arylation product 2b in 50% yield
(Table 1, entry 12). Finally, brief screening of the bases Cs2CO3,
K2CO3, KOAc and AgOAc revealed that K2CO3 was the most
suitable base for the C6 arylation reaction of pyrrolo[2,3-d]
pyrimidine.
Fagnou and co-workers established that the reactivity of aryl
iodides is sometimes reduced by the accumulation of iodide
Table 1 Optimization of direct C6 arylation of pyrrolopyrimidine 1aa
Entry
RC6H4X
Reaction conditions
Yieldb, %
1
2
3
4
5
6
7
8
4-MeOC6H4I
4-MeOC6H4I
4-MeOC6H4I
4-MeOC6H4I
4-MeOC6H4I
4-MeOC6H4I
4-MeOC6H4I
4-MeOC6H4Br
4-MeOC6H4Br
4-MeOC6H4Br
4-CNC6H4I
Pd(OAc)2, CuI, Cs2CO3
Pd(OAc)2, P(2-biPh)Cy2, K2CO3
2a, 21c
2a, 34
2a, 80
2a, 40d
2a, 46
2a, 51
2a, 78
2a, 79
2a, 2e
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3
Pd(OAc)2, PCy3$HBF4, K2CO3
Pd(OAc)2, P(2-biPh)Cy2, PivOH, K2CO3
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3, Ag2CO3
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3
Pd(OAc)2, PCy3, PivOH, K2CO3
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3, dioxane
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3
Pd(OAc)2, PCy3$HBF4, PivOH, K2CO3
9
10
11
12
2a, 10e
2b, 17
2b, 50
4-CNC6H4Br
a
Unless otherwise specied, all reactions were carried out using 5 mol% Pd(OAc)2, 10 mol% PCy3$HBF4 or P(2-biPh)Cy2, 30 mol% PivOH, 1.5 equiv.
RC6H4X, 3 equiv. K2CO3 in DMA at 170 ꢀC, 72 h, argon. b Isolated yields. c 5 mol% Pd(OAc)2, 3 equiv. CuI, 2 equiv. RC6H4X, 2.5 equiv. Cs2CO3 argon.
d
2 mol% Pd(OAc)2, 4 mol% PCy3$HBF4. e The rest of 1a recovered.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 35966–35974 | 35967

View Article Online
RSC Advances
Paper
Having established that the optimal reaction conditions ortho- and/or para-positions of the benzene ring were able to
were Pd(OAc)2/PCy3$HBF4/PivOH as the catalyst system, K2CO3 undergo arylation and furnished the corresponding products 2a–s
as the base and DMA as the solvent, we next turned our atten- in moderate to good yields. The reaction showed good compati-
tion to the scope of the direct arylation of 7-methyl-2,4-diary- bility with many valuable functional groups, including methoxy,
lpyrrolo[2,3-d]pyrimidines (1a–c) with aryl bromides, because of cyano, nitro, dimethylamino, uoro, and triuoromethyl substit-
their stability and ease of preparation on the laboratory scale.
uents. Pyrrolo[2,3-d]pyrimidines also reacted with sterically
As shown in Scheme 1, a variety of aryl bromides with either encumbered aryl bromides, such as 2-bromotoluene, 1-bromo-
electron-donating or electron-withdrawing groups attached at the 2,6-dimethylbenzene or 1-bromo-2,4-di(triuoromethyl)benzene
Scheme 1 Scope of C6 arylation of 7-methyl-2,4-diarylpyrrolo[2,3-d]pyrimidines. (a) Reaction conditions (isolated yields): compound 1a–c (70
mg), Pd(OAc)2 (5 mol%), PCy3$HBF4 (10 mol%), PivOH (30 mol%), aryl halide (1.5 equiv.), K2CO3 (3 equiv.), DMA. (b) Compound 3 (7–10 mg) was
also isolated. (c) Compound 4 (4 mg) was also isolated.
35968 | RSC Adv., 2014, 4, 35966–35974
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
p-extended conjugated systems. The results presented here may
aid materials and pharmaceutical research programs.
Experimental section
General procedure for the synthesis of 2,4-diaryl-7-
methylpyrrolo[2,3-d]pyrimidines 1a–c
2
Structures of 7,70-dimethyl-2,204,40-tetraphenyl-7H,70H-
A
solution of 2,4-dichloro-7-methylpyrrolo[2,3-d]pyrimidine
Fig.
5,50bipyrrolo[2,3-d]pyrimidine (3) and 7-methyl-5,6-di(4-nitrophenyl)-
2,4-diphenyl-7H-pyrrolo[2,3-d]pyrimidine (4).
(150 mg, 0.74 mmol) in anhydrous dioxane (5 mL) was ushed
with argon and Pd(OAc)2 (3.32 mg, 0.015 mmol, 2 mol%) and
(2-biphenyl)dicyclohexylphosphine (10.4 mg, 0.03 mmol, 4
mol%) were added under stirring and argon ow. Aer 10 min,
arylboronic acid (1.78 mmol, 2.4 equiv.) and K3PO4 (0.76 g, 3.56
mmol, 4.8 equiv.) were added. The reaction mixture was stirred
under reux. Then dioxane was evaporated under reduced
pressure to dryness and water (5 mL) was added to dissolve
inorganic salts. The obtained solution was extracted with
chloroform (3 ꢁ 25 mL), the organic layer was dried over
Na2SO4, and the chloroform removed by distillation under
reduced pressure. The residue was puried by column chro-
matography using benzene as an eluent.
to afford the corresponding products 2k–m and 2p in 50–79%
yields.
The arylation reaction of pyrrolo[2,3-d]pyrimidines 1a–c can
occur at position 5 or 6 of the pyrrolopyrimidine. However,
structural elucidation of the products by NMR spectroscopy
showed that the arylation reaction is site-selective and only
6-aryl derivatives were obtained. In the 1H NMR spectra of
compounds 2, the pyrrole 5-H proton signal remains at 6.8–7.0
ppm, almost in the same place as in the starting compounds 1.
Moreover, NOESY spectra of the products showed two main
types of cross-signal: between the N-methyl group and the ortho-
protons of the aromatic ring at position 6; and between the 5-H
proton of the pyrrole ring and ortho-protons of the aromatic
rings at positions 4 and 6 of the pyrrolopyrimidine. Addition-
ally, in the NOESY spectra no interaction between the N-methyl
group protons and the pyrrole ring proton was observed. This
incontrovertibly proved that only C6 arylated products were
obtained.
Nevertheless, in some cases, the formation of two types of
byproducts was observed (Fig. 2). The rst one was identied as
dimerization product 3. This byproduct in small amounts (up to
7%) was formed in the reaction of pyrrolo[2,3-d]pyrimidine 1a
with 1-bromo-4-triuoromethyl-, 1-bromo-4-dimethylamino-
and 1-bromo-2,6-dimethylbenzenes. Compound 3, is probably
formed during the side-reaction of the palladium-catalyzed
oxidative C5–H activation with Pd(OAc)2. Another byproduct,
5,6-diarylated derivative 4 (3%), was observed only in the reac-
tion of compound 1a with 4-nitrophenyl bromide (Fig. 2).
Formation of these byproducts caused some problems in the
purication of the target compounds. Therefore, lower nal
yields of the corresponding C6 arylation products 2f, 2j, and 2l
were obtained.
7-Methyl-2,4-diphenyl-7H-pyrrolo[2,3-d]pyrimidine (1a)
Aer 15 min, compound 1a was obtained as a yellowish solid
(190 mg, 90%), mp 159.8–161.4 ꢀC. Lit.20 mp 159–160 ꢀC. All
spectra matched literature values. H NMR (400 MHz, CDCl3):
4.00 (3H, s, NCH3), 6.85 [1H, d, J ¼ 4 Hz, 5-H (pp)], 7.25 [1H, d, J
¼ 4 Hz, 6-H (pp)], 7.46–7.63 [6H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph)], 8.31
[2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.72 [2H, dm, J ¼ 8 Hz, 2,6-H (2-
Ph)] ppm. 13C NMR (100 MHz, CDCl3): 31.1, 100.3, 113.9, 128.1,
128.4, 128.7, 129.0, 129.6, 129.9, 130.0, 138.8, 139.1, 153.1,
157.0, 157.6 ppm. HRMS-ESI: m/z calcd. for MH+ (C19H16N3):
286.1339, found: 286.1342.
1
2,4-Di(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]
pyrimidine (1b)
Aer 4 h, compound 1b was obtained as a yellowish solid (182
mg, 71%), mp 138.4–139.7 ꢀC. 1H NMR (400 MHz, CDCl3): 3.92
(3H, s, OCH3), 3.93 (3H, s, OCH3), 3.96 (3H, s, NCH3), 6.81 [1H,
d, J ¼ 4 Hz, 5-H (pp)], 7.05 [2H, d, J ¼ 8 Hz, 3,5-H (2-Ph)], 7.11
[2H, d, J ¼ 8 Hz, 3,5-H (4-Ph)], 7.19 [1H, d, J ¼ 4 Hz, 6-H (pp)],
8.29 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.66 [2H, dm, J ¼ 8 Hz, 2,6-
H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 31.0, 55.4, 55.42,
100.3, 112.9, 113.7, 114.1, 129.2, 129.5, 130.5, 131.6, 132.1,
153.1, 156.5, 157.5, 161.0, 161.1 ppm. HRMS-ESI: m/z calcd. for
MH+ (C21H20N3O2): 346.1550, found: 346.1548.
The yields of the selective C6 arylation were dramatically
lower without a palladium-pivalate co-catalyst combination.
These results suggest that the C6 arylation proceeds via a
concerted metallation–deprotonation mechanism.19
2,4-Di[4-(9H-carbazol-9-yl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]
pyrimidine (1c)
Aer 9.5 h, compound 1c was obtained as a reddish solid (410
mg, 90%), mp 284–285.8 C. H NMR (400 MHz, CDCl3): 4.08
Conclusion
1
ꢀ
In summary, an efficient regioselective Pd-catalyzed direct ary- (3H, s, NCH3), 7.00 [1H, d, J ¼ 4 Hz, 5-H (pp)], 7.33–7.39 [m, 5H,
lation of 7-methyl-2,4-diarylpyrrolo[2,3-d]pyrimidines with aryl 6-H (pp), 2 ꢁ 3,6-H (2-carb., 4-carb.)], 7.46–7.52 [4H, m, 2 ꢁ 2,7-
bromides has been developed. The procedure tolerates many H (2-carb., 4-carb.)], 7.58–7.62 [4H, m, 2 ꢁ 1,8-H (2-carb.,
functional groups and allows the generation of a wide library of 4-carb.)], 7.79 [2H, d, J ¼ 8 Hz, 3,5-H (4-Ph)], 7.86 [2H, d, J ¼ 8
novel pyrrolo[2,3-d]pyrimidine derivatives, including those with Hz, 3,5-H (2-Ph)], 8.20–8.23 [4H, m, 2 ꢁ 4,5-H (2-carb., 4-carb.)],
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 35966–35974 | 35969

View Article Online
RSC Advances
Paper
8.61 [2H, d, J ¼ 8.4 Hz, 2,6-H (4-Ph)], 9.00 [2H, d, J ¼ 8.7 Hz, 2,6- 100.0, 114.2, 128.1, 128.4, 128.7, 128.76, 128.8, 129.0, 129.1,
H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 31.3, 100.3, 109.9, 129.5, 129.9, 131.7, 138.9, 139.2, 143.0, 154.7, 156.3, 157.5 ppm.
110.0, 114.1, 120.0, 120.3, 120.4, 120.42, 123.5, 123.7, 126.0, HRMS-ESI: m/z calcd. for MH+ (C25H20N3): 362.1652, found:
126.1, 126.9, 127.1, 129.7, 130.56, 130.6, 137.6, 138.1, 138.9, 362.1652.
139.4, 140.7, 140.8, 153.3, 156.1, 157.1 ppm. HRMS-ESI: m/z
calcd. for MH+ (C43H30N5): 616.2496, found: 616.2490.
7-Methyl-6-(4-methylphenyl)-2,4-diphenyl-7H-pyrrolo[2,3-d]
pyrimidine (2d)
General procedure for C–H arylation
Product 2d was obtained as a bright yellow solid (63 mg, 68%),
7-Methyl-2,4-diphenylpyrrolo[2,3-d]pyrimidine (1a) (70 mg, mp 196–197.8 ꢀC. 1H NMR (400 MHz, CDCl3): 2.48 (3H, s, CH3),
0.245 mmol), Pd(OAc)2 (2.75 mg, 0.0125 mmol, 5 mol%), 3.99 (3H, s, NCH3), 6.88 [1H, s, 5-H (pp)], 7.36 [2H, dm, J ¼ 8 Hz,
PCy3$HBF4 (9.0 mg, 0.0244 mmol, 10 mol%), PivOH (7.5 mg, 3,5-H (6-Ph)], 7.46–7.62 [8H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph), 2,6-H
0.0734 mmol, 30 mol%), aryl halide (0.37 mmol, 1.5 equiv.) and (6-Ph)], 8.34 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.74 [2H, dm, J ¼ 8
K2CO3 (100 mg, 0.724 mmol, 3 equiv.) and DMA (1–2 mL) were Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 21.4, 29.9,
placed in a screw-cap vial equipped with a magnetic stir bar. 99.6, 114.3, 128.0, 128.4, 128.7, 128.8, 128.98, 128.99, 129.4,
The vial was purged with argon and the reaction mixture was 129.5, 129.8, 138.8, 139.0, 139.3, 143.2, 154.7, 156.1, 157.3 ppm.
stirred vigorously at 170 ꢀC for 72 h. Aer completion of the HRMS-ESI: m/z calcd. for MH+ (C26H22N3): 376.1808, found:
reaction, water (10 mL) was added and the aqueous solution 376.1814.
was extracted with ethyl acetate (3 ꢁ 25 mL). The combined
extract was dried with anhydrous Na2SO4, ethyl acetate removed
by distillation under reduced pressure, and the residue was
puried by column chromatography using a gradient of hexane/
benzene / benzene.
6-(4-Triuoromethylphenyl)-7-methyl-2,4-diphenyl-7H-pyrrolo
[2,3-d]pyrimidine (2e)
Product 2e was obtained as a bright yellow solid (66 mg, 66%),
mp 200–201.7 ꢀC. Compound 3 was also isolated (7 mg, 5%). 1H
NMR (400 MHz, CDCl3): 4.00 (3H, s, NCH3), 6.97 [1H, s, 5-H
(pp)], 7.49–7.61 [6H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph)], 7.75 [2H, dm,
J ¼ 8 Hz, 2,6-H (6-Ph)], 7.81 [2H, dm, J ¼ 8 Hz, 3,5-H (6-Ph)], 8.33
6-(4-Methoxyphenyl)-7-methyl-2,4-diphenyl-7H-pyrrolo[2,3-d]
pyrimidine (2a)
Product 2a was obtained as a yellow solid (76 mg, 79%), mp [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.75 [2H, dm, J ¼ 8 Hz, 2,6-H (2-
152.2–153.8 ꢀC. 1H NMR (400 MHz, CDCl3): 3.92 (3H, s, OCH3), Ph)] ppm 13C NMR (100 MHz, CDCl3): 30.1, 101.2, 114.0, 124.0 (J
3.98 (3H, s, NCH3), 6.85 [1H, s, 5-H (pp)], 7.07 [2H, dm, J ¼ 8 Hz, ¼ 273 Hz), 125.8 (J ¼ 4 Hz), 128.1, 128.4, 128.7, 129.0, 129.3,
3,5-H (6-Ph)], 7.48–7.62 [8H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph), 2,6-H 129.7, 130.1, 130.7 (J ¼ 33 Hz), 135.3, 138.7, 139.0, 141.1, 154.8,
(6-Ph)], 8.35 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.74 [2H, dm, J ¼ 8 156.9, 157.9 ppm. 19F NMR (376 MHz, CDCl3): ꢂ62.65 (CF3)
Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 29.9, 55.4, ppm. HRMS-ESI: m/z calcd. for MH+ (C26H19F3N3): 430.1526,
99.3, 114.27, 114.3, 124.1, 128.0, 128.4, 128.7, 129.0, 129.4, found: 430.1531.
129.8, 130.4, 139.0, 139.3, 143.0, 154.6, 155.9, 157.2, 160.1 ppm.
HRMS-ESI: m/z calcd. for MH+ (C26H22N3O): 392.1757, found:
6-[4-((Dimethylamino)phenyl)]-7-methyl-2,4-diphenyl-7H-
392.1767.
pyrrolo[2,3-d]pyrimidine (2f)
Product 2f was obtained as a dark yellow solid (55 mg, 56%), mp
214.4–215.5 C. Compound 3 was also isolated (7 mg, 5%). H
NMR (400 MHz, CDCl3): 3.07 (6H, s, N(CH3)2), 4.00 (3H, s,
6-(4-Cyanophenyl)-7-methyl-2,4-diphenyl-7H-pyrrolo[2,3-d]
pyrimidine (2b)
1
ꢀ
Product 2b was obtained as a yellowish green solid (47 mg, NCH3), 6.83–6.86 [3H, m, 5-H (pp), 3,5-H (6-Ph)], 7.49–7.61 [8H,
50%), mp 225–226.3 ꢀC. 1H NMR (400 MHz, CDCl3): 4.02 (3H, s, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph), 2,6-H (6-Ph)], 8.37 [2H, dm, J ¼ 8 Hz,
NCH3), 7.00 [1H, s, 5-H (pp)], 7.50–7.64 [6H, m, 2 ꢁ 3-5-H (2-Ph, 2,6-H (4-Ph)], 8.75 [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C
4-Ph)], 7.75 [2H, dm, J ¼ 8 Hz, 2,6-H (6-Ph)], 7.84 [2H, dm, J ¼ 8 NMR (100 MHz, CDCl3): 30.0, 40.4, 98.3, 112.1, 114.6, 119.1,
Hz, 3,5-H (6-Ph)], 8.32 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.74 [2H, 128.0, 128.4, 128.6, 129.0, 129.3, 129.6, 130.0, 139.2, 139.4,
dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 144.0, 150.6, 154.7, 155.3, 156.8 ppm. HRMS-ESI: m/z calcd. for
30.2, 101.8, 112.2, 114.0, 118.5, 127.9, 128.2, 128.4, 128.8, 129.0, MH+ (C27H25N4): 405.2074, found: 405.2077.
129.4, 129.8, 130.2, 132.6, 132.9, 138.5, 138.8, 155.0, 157.3, 158.2
ppm. HRMS-ESI: m/z calcd. for MH+ (C26H19N4): 387.1603,
6-(4-Fluorophenyl)-7-methyl-2,4-diphenyl-7H-pyrrolo[2,3-d]
found: 387.1604.
pyrimidine (2g)
Product 2g was obtained as a yellowish solid (67 mg, 72%), mp
150–151.4 C. H NMR (400 MHz, CDCl3): 3.98 (3H, s, NCH3),
7-Methyl-2,4,6-triphenyl-7H-pyrrolo[2,3-d]pyrimidine (2c)
1
ꢀ
Product 2c was obtained as a yellowish solid (71 mg, 80%), mp 6.88 [1H, s, 5-H (pp)], 7.23–7.27 [2H, m, 3,5-H (6-Ph)], 7.48–7.62
1
ꢀ
134–134.9 C. H NMR (400 MHz, CDCl3): 4.00 (3H, s, NCH3), [8H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph), 2,6-H (6-Ph)], 8.34 [2H, dm, J ¼ 8
6.92 [1H, s, 5-H (pp)], 7.49–7.64 [11H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph), Hz, 2,6-H (4-Ph)], 8.74 [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13
C
2-6-H (6-Ph)], 8.36 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.75 [2H, dm, NMR (100 MHz, CDCl3): 29.9, 100.1, 114.1, 115.9 [d, J ¼ 22 Hz,
J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 30.0, 3,5-C (6-Ph)], 127.84 [d, J ¼ 4 Hz, 1-C(6-Ph)], 128.1, 128.4, 128.7,
35970 | RSC Adv., 2014, 4, 35966–35974
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
129.0, 129.6, 129.9, 130.9 [d, J ¼ 8 Hz, 2,6-C (6-Ph)], 138.8, 139.1,
141.9, 154.6, 156.4, 157.6, 163.1 [d, J ¼ 247 Hz, 4-C (6-Ph)] ppm.
19F NMR (376 MHz, CDCl3): ꢂ112.17 (F) ppm. HRMS-ESI: m/z
calcd. for MH+ (C25H19FN3): 380.1558, found: 380.1559.
7-Methyl-6-(2,6-dimethylphenyl)-2,4-diphenyl-7H-pyrrolo[2,3-
d]pyrimidine (2l)
Product 2l was obtained as a colorless oil (48 mg, 50%).
Compound 3 was also isolated (10 mg, 7%). 1H NMR (400 MHz,
CDCl3): 2.16 (6H, s, 2 ꢁ CH3), 3.67 (3H, s, NCH3), 6.77 [1H, s,
5-H (pp)], 7.22–7.34 [3H, m, 3-5-H (6-Ph)], 7.51–7.61 [6H, m, 2 ꢁ
3-5-H (2-Ph. 4-Ph)], 8.38 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.76
[2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz,
CDCl3): 20.4, 28.6, 99.5, 114.3, 127.5, 128.0, 128.4, 128.7, 129.1,
129.2, 129.5, 129.8, 131.1, 138.4, 139.0, 139.2, 141.0, 153.7,
156.0, 157.1 ppm. HRMS-ESI: m/z calcd. for MH+ (C27H24N3):
390.1965, found: 390.1972.
6-(Biphenyl-4-yl)-7-methyl-2,4-diphenyl-7H-pyrrolo[2,3-d]
pyrimidine (2h)
Product 2h was obtained as a yellowish solid (76 mg, 70%), mp
1
ꢀ
242.3–244 C. H NMR (400 MHz, CDCl3): 4.06 (3H, s, NCH3),
6.97 [1H, s, 5-H (pp)], 7.40–7.79 [15H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph),
2,3,5,6,20-60-H (6-biPh)], 8.36 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)],
8.75 [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz,
CDCl3): 30.1, 100.1, 114.3, 127.1, 127.5, 127.8, 128.1, 128.4,
128.7, 128.9, 129.0, 129.4, 129.5, 129.9, 130.6, 138.9, 139.2,
140.3, 141.6, 142.7, 154.8, 156.3, 157.5 ppm. HRMS-ESI: m/z
calcd. for MH+ (C31H24N3): 438.1965, found: 438.1970.
6-[2,4-Di(triuoromethyl)phenyl]-7-methyl-2,4-diphenyl-7H-
pyrrolo[2,3-d]pyrimidine (2m)
Product 2m was obtained as a colorless solid (79 mg, 65%), mp
1
ꢀ
189–190.8 C. H NMR (400 MHz, CDCl3): 3.74 (3H, s, NCH3),
6.93 [1H, s, 5-H (pp)], 7.50–7.62 [6H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph)],
7.69 [1H, d, J ¼ 8 Hz, 5-H (6-Ph)], 7.99 [1H, d, J ¼ 8 Hz, 6-H (6-
Ph)], 8.16 [1H, s, 3-H (6-Ph)], 8.32 [2H, dm, J ¼ 8 Hz, 2,6-H (4-
Ph)], 8.75 [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100
MHz, CDCl3): 29.3, 102.5, 113.6, 122.8 (J ¼ 273 Hz), 123.1 (J ¼
271 Hz), 123.79 (J ¼ 4 Hz), 123.84 (J ¼ 4 Hz), 128.1, 128.41,
128.42, 128.8, 129.0, 129.8, 130.1, 131.8 (J ¼ 31 Hz), 132.0 (J ¼ 34
Hz), 133.76, 133.77, 134.3, 136.3, 138.6, 138.9, 153.8, 157.3,
158.2 ppm. 19F NMR (376 MHz, CDCl3): ꢂ59.11 (CF3), ꢂ63.00
(CF3) ppm. HRMS-ESI: m/z calcd. for MH+ (C27H18F6N3):
498.1399, found: 498.1396.
6-[4-(9H-Carbazol-9-yl)phenyl]-7-methyl-2,4-diphenyl-7H-
pyrrolo[2,3-d]pyrimidine (2i)
Product 2i was obtained as a yellowish solid (107 mg, 83%), mp
258.5–259.8 ꢀC. 1H NMR (400 MHz, CDCl3): 4.12 (3H, s, NCH3),
7.04 [1H, s, 5-H (pp)], 7.37–7.64 [12H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph),
1-3, 6-8-H (6-carb.)], 7.77 [2H, dm, J ¼ 8 Hz, 3,5-H (6-Ph)], 7.87
[2H, dm, J ¼ 8 Hz, 2,6-H (6-Ph)], 8.21 [2H, dm, J ¼ 8 Hz, 4,5-H (6-
carb.)], 8.39 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.78 [2H, dm, J ¼ 8
Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 30.2, 100.6,
109.8, 114.2, 120.3, 120.5, 123.7, 126.1, 127.2, 128.1, 128.4,
128.8, 129.0, 129.6, 130.0, 130.5, 130.6, 138.2, 138.8, 139.1,
140.6, 142.0, 154.9, 156.6, 157.7 ppm. HRMS-ESI: m/z calcd. for
MH+ (C37H27N4): 527.2230, found: 527.2242.
7-Methyl-6-[(4-diphenylamino)phenyl]-2,4-diphenyl-7H-
pyrrolo[2,3-d]pyrimidine (2n)
7-Methyl-6-(4-nitrophenyl)-2,4-diphenyl-7H-pyrrolo[2,3-d]
Product 2n was obtained as a bright yellow lm (100 mg, 77%).
1H NMR (400 MHz, CDCl3): 4.03 (3H, s, NCH3), 6.88 [1H, s, 5-H
(pp)], 7.12–7.22 [8H, m, 3,5-H (6-Ph), 2 ꢁ 20,40,60-H (NPh2)],
7.32–7.36 [4H, m, 2 ꢁ 30,50-H (NPh2)], 7.46–7.62 [8H, m, 2,6-H (6-
Ph), 2 ꢁ 3-5-H (2-Ph, 4-Ph)], 8.35 [2H, dm, J ¼ 8 Hz, 2,6-H (4-
Ph)], 8.74 [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100
MHz, CDCl3): 30.1, 99.3, 114.4, 122.5, 123.7, 124.7, 125.0, 125.1,
128.0, 128.4, 128.7, 129.0, 129.4, 129.5, 129.8, 139.0, 139.3,
143.1, 147.3, 148.4, 154.7, 155.9, 157.2 ppm. HRMS-ESI: m/z
calcd. for MH+ (C37H29N4): 529.2387, found: 529.2385.
pyrimidine (2j)
Product 2j was obtained as an orange solid (52 mg, 52%), mp
1
ꢀ
263.1–264.5 C. Compound 4 was also isolated (4 mg, 3%). H
NMR (400 MHz, CDCl3): 4.05 (3H, s, NCH3), 7.05 [1H, s, 5-H
(pp)], 7.52–7.62 [6H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph)], 7.82 [2H, dm, J
¼ 8 Hz, 2,6-H (6-Ph)], 8.33 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.41
[2H, dm, J ¼ 8 Hz, 3,5-H (6-Ph)], 8.74 [2H, dm, J ¼ 8 Hz, 2,6-H
(2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 30.3, 102.3, 114.0,
124.1, 128.2, 128.4, 128.8, 129.0, 129.5, 129.9, 130.2, 138.1,
138.5, 138.8, 140.1, 147.6, 155.1, 157.5, 158.4 ppm. HRMS-ESI:
m/z calcd. for MH+ (C25H19N4O2): 407.1503, found: 407.1506.
7-Methyl-6-(naphthalen-2-yl)-2,4-diphenyl-7H-pyrrolo[2,3-d]
7-Methyl-6-(2-methylphenyl)-2,4-diphenyl-7H-pyrrolo[2,3-d]
pyrimidine (2o)
pyrimidine (2k)
Product 2o was obtained as a yellow solid (63 mg, 62%), mp
Product 2k was obtained as a yellowish oil (73 mg, 79%). 1H 185.5–187 C. H NMR (400 MHz, CDCl3): 4.06 (3H, s, NCH3),
NMR (400 MHz, CDCl3): 2.30 (3H, s, CH3), 3.76 (3H, s, NCH3), 7.02 [1H, s, 5-H (pp)], 7.50–7.62 [8H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph),
6.84 [1H, s, 5-H (pp)], 7.36–7.64 [10H, m, 2 ꢁ 3-5-H (2-Ph, 4-Ph), 4,5-H (6-naph)], 7.73 [1H, dd, J ¼ 8 Hz, 8-H (6-naph)], 7.95–7.98
3-6-H (6-Ph)], 8.39 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.79 [2H, dm, [2H, m, 3,6-H (6-naph)], 8.01 [1H, d, J ¼ 8 Hz, 7-H (6-naph)], 8.10
J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 20.0, [1H, s, 2-H (6-naph)], 8.38 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.77
29.2, 100.1, 114.2, 125.9, 128.1, 128.4, 128.7, 129.1, 129.4, 129.5, [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz,
129.9, 130.4, 130.8, 131.4, 137.9, 139.0, 139.3, 142.3, 153.9, CDCl3): 30.2, 100.4, 114.3, 126.5, 126.86, 126.9, 127.9, 128.1,
156.2, 157.4 ppm. HRMS-ESI: m/z calcd. for MH+ (C26H22N3): 128.3, 128.4, 128.41, 128.5, 128.7, 129.0, 129.1, 129.6, 129.9,
1
ꢀ
376.1808, found: 376.1811.
133.1, 133.2, 138.9, 139.2, 143.1, 154.8, 156.4, 157.5 ppm.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 35966–35974 | 35971

View Article Online
RSC Advances
Paper
HRMS-ESI: m/z calcd. for MH+ (C29H22N3): 412.1808, found: 138.1, 140.6, 141.3, 156.1, 161.0, 161.2 ppm. HRMS-ESI: m/z
412.1812.
calcd. for MH+ (C39H31N4O2): 587.2442, found: 587.2444.
6-(2,4-Di(triuoromethyl)phenyl)-2,4-di(4-methoxyphenyl)-7-
methyl-7H-pyrrolo[2,3-d]pyrimidine (2p)
2,4-Di(4-(9H-carbazol-9-yl)phenyl)-7-methyl-6-(4-
methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine (2s)
Compound 2p was synthesized by the general procedure for
C–H arylation, starting from 2,4-di(4-methoxyphenyl)-7-meth-
ylpyrrolo[2,3-d]pyrimidine (1b) (70 mg, 0.20 mmol). Aer 72 h
Compound 2s was synthesized by the general procedure for
C–H arylation, starting from 2,4-di(4-(9H-carbazol-9-yl)phenyl)-
7-methylpyrrolo[2,3-d]pyrimidine (1c) (70 mg, 0.13 mmol). Aer
ꢀ
ꢀ
(170 C) product 2p was obtained as a colorless solid (87 mg,
70 h (170 C) product 2s was obtained as a yellowish solid (47
77%), mp 185.5–186.2 ꢀC. 1H NMR (400 MHz, CDCl3): 3.71 (3H,
s, NCH3), 3.93 (6H, s, 2 ꢁ OCH3), 6.88 [1H, s, 5-H (pp)], 7.07 [2H,
d, J ¼ 8 Hz, 3,5-H (2-Ph)], 7.11 [2H, d, J ¼ 8 Hz, 3,5-H (4-Ph)], 7.68
[1H, d, J ¼ 8 Hz, 5-H (6-Ph)], 7.98 [1H, d, J ¼ 8 Hz, 6-H (6-Ph)],
8.15 [1H, s, 3-H (6-Ph)], 8.29 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)],
8.68 [2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz,
CDCl3): 29.2, 55.4, 55.43, 102.6, 112.6, 112.9, 113.7, 114.3, 122.9
(J ¼ 272 Hz), 123.2 (J ¼ 272 Hz), 123.77 (J ¼ 4 Hz), 123.8 (J ¼ 4
Hz), 124.2, 124.5, 128.3, 129.6, 130.5, 131.3, 131.7 (J ¼ 34 Hz),
131.8, 131.9 (J ¼ 34 Hz), 133.8, 133.81, 134.6, 135.4153.9, 156.8,
158.1, 161.1, 161.3 ppm. 19F NMR (376 MHz, CDCl3): ꢂ59.07
(CF3), ꢂ62.97 (CF3) ppm. HRMS-ESI: m/z calcd. for MH+
(C29H22F6N3O2): 558.1611, found: 558.1613.
mg, 50%), mp 305–306 ꢀC. 1H NMR (400 MHz, CDCl3): 2.52 (3H,
s, CH3), 4.07 (3H, s, NCH3), 7.03 [1H, s, 5-H (pp)], 7.34–7.52
[10H, m, 3,5-H (6-Ph), 2 ꢁ 2,7-H (2-carb., 4-carb.), 2 ꢁ 3,6-H
(2-carb., 4-carb.)], 7.58–7.62 [6H, m, 2,6-H (6-Ph), 2 ꢁ 1,8-H
(2-carb., 4-carb.)], 7.80 [2H, dm, J ¼ 8 Hz, 3,5-H (2-Ph)], 7.86 [2H,
dm, J ¼ 8 Hz, 3,5-H (6-Ph)], 8.22 [4H, m, 2 ꢁ 4,5-H (2-carb., 4-
carb.)], 8.65 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 9.02 [2H, dm, J ¼ 8
Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 21.4, 30.1,
99.6, 109.9, 110.0, 114.4, 120.0, 120.2, 120.35, 120.42, 123.5,
123.6, 126.0, 126.1, 126.9, 127.1, 128.6, 129.0, 129.6, 129.62,
130.5, 137.8, 138.2, 138.8, 139.1, 139.3, 140.7, 140.8, 143.9,
154.8, 155.1, 156.7 ppm. HRMS-ESI: m/z calcd. for MH+
(C50H36N5): 706.2965, found: 706.2961.
7,70-Dimethyl-2,204,40-tetraphenyl-7H,70H-5,50bipyrrolo[2,3-d]
6-[4-((Dimethylamino)phenyl)]-2,4-di(4-methoxyphenyl)-7-
methyl-7H-pyrrolo[2,3-d]pyrimidine (2q)
pyrimidine (3)
1
ꢀ
Compound 2q was synthesized by the general procedure for
C–H arylation, starting from 2,4-di(4-methoxyphenyl)-7-meth-
ylpyrrolo[2,3-d]pyrimidine (1b) (70 mg, 0.20 mmol). Aer 72 h
(170 ꢀC) product 2q was obtained as a yellow lm (72 mg, 77%).
1H NMR (400 MHz, CDCl3): 3.07 (6H, s, N(CH3)2), 3.92 (3H, s,
OCH3), 3.94 (3H, s, OCH3), 3.97 (3H, s, NCH3), 6.78 [1H, s, 5-H
(pp)], 6.86 [2H, d, J ¼ 8 Hz, 3,5-H (6-Ph)], 7.06 [2H, d, J ¼ 8 Hz,
3,5-H (2-Ph)], 7.11 [2H, d, J ¼ 8 Hz, 3,5-H (4-Ph)], 7.50 [2H, d, J ¼
8 Hz, 3,5-H (6-Ph)], 8.33 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.67
[2H, dm, J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz,
CDCl3): 29.9, 40.4, 55.4, 55.42, 98.4, 112.1, 113.5, 113.6, 114.0,
119.3, 129.38, 129.9, 130.4, 131.9, 132.3, 143.3, 150.5, 154.6,
154.9, 156.7, 160.8, 160.9 ppm. HRMS-ESI: m/z calcd. for MH+
(C29H29N4O2): 465.2285, found: 465.2289.
Yellow solid, mp 269–270 C. H NMR (400 MHz, CDCl3): 4.00
(3H, s, NCH3), 7.13 [1H, s, 6-H (pp)], 7.55–7.64 [6H, m, 2 ꢁ 3-5-H
(2-Ph, 4-Ph)], 8.36 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.76 [2H, dm,
J ¼ 8 Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 29.9,
103.6, 113.8, 129.2, 128.5, 128.9, 129.1, 129.9, 130.2, 131.9,
138.5, 138.8, 154.4, 157.5, 158.5 ppm. HRMS-ESI: m/z calcd. for
MH+ (C38H29N6): 569.2448, found: 569.2462.
7-Methyl-5,6-di(4-nitrophenyl)-2,4-diphenyl-7H-pyrrolo[2,3-d]
pyrimidine (4)
Yellow solid, mp 274.5–275 ꢀC. 1H NMR (400 MHz, CDCl3): 3.96
(3H, s, NCH3), 6.90 [2H, dm, J ¼ 8 Hz, 2,6-H (5-Ph)], 7.11–7.15
[2H, m, 2 ꢁ 4-H (2-Ph, 4-Ph)], 7.37–7.55 [8H, m, 2,6-H (6-Ph),
3,5-H (2-Ph), 2,3,5,6-H (4-Ph)], 7.82 [2H, dm, J ¼ 8 Hz, 3,5-H (5-
Ph)], 8.29 [2H, dm, J ¼ 8 Hz, 3,5-H (6-Ph)], 8.73 [2H, dm, J ¼ 8
Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 30.1, 112.7,
114.0, 122.9, 124.0, 127.6, 128.3, 128.5, 129.4, 129.6, 130.2,
131.2, 131.8, 136.6, 137.2, 137.5, 138.3, 140.6, 146.1, 148.0,
153.9, 158.6, 160.0 ppm. HRMS-ESI: m/z calcd. for MH+
(C31H22N5O4): 528.1666, found: 528.1675.
6-[4-(9H-Carbazol-9-yl)phenyl]-2,4-di(4-methoxyphenyl)-7-
methyl-7H-pyrrolo[2,3-d]pyrimidine (2r)
Compound 2r was synthesized by the general procedure for C–H
arylation, starting from 2,4-di(4-methoxyphenyl)-7-methyl-
pyrrolo[2,3-d]pyrimidine (1b) (70 mg, 0.20 mmol). Aer 72 h
(170 ꢀC) product 2r was obtained as a yellow solid (83 mg, 70%),
mp 265.2–266.6 ꢀC. 1H NMR (400 MHz, CDCl3): 3.94 (3H, s,
OCH3), 3.95 (3H, s, OCH3), 4.10 (3H, s, NCH3), 7.01 [1H, s, 5-H
(pp)], 7.08 [2H, d, J ¼ 8 Hz, 3,5-H (4-Ph)], 7.14 [2H, d, J ¼ 8 Hz,
3,5-H (2-Ph)], 7.34–7.38 [2H, m, 3,6-H (6-carb.)], 7.47–7.50 [2H,
m, 2,7-H (6-carb.)], 7.77 [2H, dm, J ¼ 8 Hz, 3,5-H (6-Ph)], 7.86
[2H, dm, J ¼ 8 Hz, 2,6-H (6-Ph)], 8.21 [2H, dm, J ¼ 8 Hz, 4,5-H (6-
carb.)], 8.37 [2H, dm, J ¼ 8 Hz, 2,6-H (4-Ph)], 8.71 [2H, dm, J ¼ 8
Hz, 2,6-H (2-Ph)] ppm. 13C NMR (100 MHz, CDCl3): 30.1, 55.4,
55.45, 100.7, 109.8, 113.2, 113.7, 114.1, 120.3, 120.5, 123.6,
126.1, 127.2, 129.6, 130.4, 130.5, 130.5, 130.8, 131.6, 132.0,
Acknowledgements
The research was funded by a grant (no. MIP-027/2013) from the
Research Council of Lithuania.
Notes and references
1 (a) D. J. Calderwood, D. N. Johnston, R. Munschauer and
P. Rafferty, Bioorg. Med. Chem. Lett., 2002, 12, 1683–1686;
(b) Q. Lin, D. Meloni, Y. Pan, M. Xia, J. Rodgers,
35972 | RSC Adv., 2014, 4, 35966–35974
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
S. Shepard, M. Li, L. Galya, B. Metcalf, T.-Y. Yue, P. Liu and
RSC Advances
K. M. H. Hilmy, M. M. A. Khalifa, M. Abd Allah Hawata,
R. M. AboAlzeen Keshk and A. A. El-Torgman, Eur. J. Med.
Chem., 2010, 45, 5243–5250; (c) M. S. Mohamed,
W. M. Hussein, R. P. McGeary, P. Vella, G. Schenk and
R. H. Abd El-hameed, Eur. J. Med. Chem., 2011, 46, 6075–
6082; (d) S. J. Kaspersen, C. Sørum, V. Willassen,
E. Fuglseth, E. Kjøbli, G. Bjørkøy, E. Sundby and
B. H. Hoff, Eur. J. Med. Chem., 2011, 46, 6002–6014; (e)
S. J. Kaspersen, E. Sundby, C. Charnock and B. H. Hoff,
Bioorg. Chem., 2012, 44, 35–41; (f) M. S. Mohamed,
A. G. Mostafa and R. H. Abd El-hameed, Pharmacophore,
2012, 3(1), 44–54; (g) A. Davoodnia, M. Khashi, N. Tavakoli-
Hoseini, R. Moloudi and H. Ali Zamani, Monatsh. Chem.,
2013, 144, 677–680.
J. Zhou, Org. Lett., 2009, 11, 1999–2002; (c) T. Wang,
M. W. Ledeboer, J. P. Duffy, F. G. Salituro, A. C. Pierce,
H. J. Zuccola, E. Block, D. Shlyakter, J. K. Hogan and
J. L. Bennani, Bioorg. Med. Chem. Lett., 2010, 20, 153–156;
(d) Z. Chen, A. M. Venkatesan, C. M. Dehnhardt, S. Ayral-
Kaloustian, N. Brooijmans, R. Mallon, L. Feldberg,
I. Hollander, J. Lucas, K. Yu, F. Kong and T. S. Mansour, J.
Med. Chem., 2010, 53, 3169–3182.
2 V. P. Kumar, K. M. Frey, Y. Wang, H. K. Jain, A. Gangjee and
K. S. Anderson, Bioorg. Med. Chem. Lett., 2013, 23, 5426–5428.
3 C. L. Gibson, J. K. Huggan, A. Kennedy, L. Kiefer, J. H. Lee,
C. J. Suckling, C. Clements, A. L. Harvey, W. N. Hunter and
L. B. Tulloch, Org. Biomol. Chem., 2009, 7, 1829–1842.
4 X. Y. Jiao, D. J. Kopecky, J. S. Liu, J. Q. Liu, J. C. Jaen, 13 (a) F. Wojciechowski and R. H. E. Hudson, Org. Lett., 2009,
M. G. Cardozo, R. Sharma, N. Walker, H. Wesche, S. Li,
E. Farrelly, S. H. Xiao, Z. Wang and F. Kayser, Bioorg. Med.
Chem. Lett., 2012, 22, 6212–6217.
5 (a) M. S. Mohamed, R. A. El-Donnay and R. H. El-Hameed,
Acta Pharm., 2009, 59, 145–158; (b) M. S. Mohamed,
R. Kamel and S. S. Fatahala, Eur. J. Med. Chem., 2010, 45,
2994–3004.
11(21), 4878–4881; (b) J. Quiroga, P. A. Acosta, S. Cruz,
R. Abon¸ka, B. Insuasty, M. Nogueras and J. Cobo,
Tetrahedron Lett., 2010, 51, 5443–5447; (c) S. H. Spergel,
D. R. Okoro and W. Pitts, J. Org. Chem., 2010, 75, 5316–
5319; (d) A. Mayasundari and N. Fujii, Tetrahedron Lett.,
´
2010, 51, 3597–3598; (e) V. Prieur, J. Rubio-Martınez,
M. Font-Bardia, G. Guillaumet and M. D. Pujol, Eur. J. Org.
Chem., 2014, 1514–1524.
6 (a) S. Hess, C. E. Muller, W. Frobenius, U. Reith, K.-N. Klotz
and K. Eger, J. Med. Chem., 2000, 43, 4636–4646; (b) 14 For a recent review on Pd-catalyzed cross-coupling reaction
R. J. Gillespie, I. A. Cliffe, C. E. Dawson, C. T. Dourish,
S. Gaur, A. M. Jordan, A. R. Knight, J. Lerpiniere, A. Misra,
R. M. Pratt, J. Roffey, G. C. Stratton, R. Upton, S. M. Weiss
and D. S. Williamson, Bioorg. Med. Chem. Lett., 2008, 18,
2924–2929; (c) L.-J. Gao, J. S. Schwed, L. Weizel, S. De
Jonghe, H. Stark and P. Herdewijn, Bioorg. Med. Chem.
Lett., 2013, 23, 132–137.
7 (a) P. Naus, R. Pohl, I. Votruba, P. Dzubak, M. Hajduch,
R. Ameral, G. Birkus, T. Wang, A. S. Ray, R. Mackman,
T. Cihlar and M. Hocek, J. Med. Chem., 2010, 53, 460–470;
of pyrrolo[2,3-d]pyrimidine, see: S. Tumkevicius and
J. Dodonova, Chem. Heterocycl. Compd., 2012, 48(2), 258–
279. For representative examples: (a) M. Klecka, R. Pohl,
B. Klepetarova and M. Hocek, Org. Biomol. Chem., 2009, 7,
866–868; (b) C. Xiao, C. Sun, W. Han, F. Pan, Z. Dan, Y. Li,
Z.-G. Song and Y.-H. Jin, Bioorg. Med. Chem., 2011, 19,
7100–7110; (c) A. Suzuki, K. Kimura, S. Ishioroshi, I. Saito,
N. Nemoto and Y. Saito, Tetrahedron Lett., 2013, 54, 2348–
2352; (d) R. V. Urbonas, V. Poskus, J. Bucevicius,
J. Dodonova and S. Tumkevicius, Synlett, 2013, 1383–1386.
(b) P. Perlikova, P. Pohl, I. Votruba, R. Shih, G. Birkus, 15 For recent reviews on direct C–H arylation of heteroarenes,
T. Cihlar and M. Hocek, Bioorg. Med. Chem., 2011, 19, 229–
242.
see: (a) L.-C. Campeau, R. Stuart and K. Fagnou,
Aldrichimica Acta, 2007, 40, 35–41; (b) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–
238; (c) T. Satoh and M. Miura, Chem. Lett., 2007, 36, 200–
205; (d) I.-V. Seregin and V. Gevorgyan, Chem. Soc. Rev.,
2007, 36, 1173–1193; (e) I. J. S. Fairlamb, Chem. Soc. Rev.,
2007, 36, 1036–1045; (f) L. Ackermann, R. Vicente and
A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–9826; (g)
F. Bellina and R. Rossi, Tetrahedron, 2009, 65, 10269–
10310; (h) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu,
Angew. Chem., Int. Ed., 2009, 48, 5094–5115; (i)
O. Daugulis, Top. Curr. Chem., 2010, 292, 57–84; (j)
M. Livendahl and A. M. Echavarren, Isr. J. Chem., 2010, 50,
630–651; (k) J. Roger, A. L. Gottumukkala and H. Doucet,
ChemCatChem, 2010, 2, 20–40; (l) T. W. Lyons and
M. S. Sanford, Chem. Rev., 2010, 110, 1147–1169; (m)
C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111,
1293–1314; (n) Y.-X. Su and L.-P. Sun, Mini-Rev. Org. Chem.,
2012, 9, 87–117; (o) J. Wencel-Delord and F. Glorius, Nat.
Chem., 2013, 5, 369–375; (p) F. Shibahara and T. Murai,
Asian J. Org. Chem., 2013, 2, 624–636; (q) R. Rossi,
8 (a) P. Traxler, P. R. Allegrini, R. Brandt, J. Brueggen,
R. Cozens, D. Fabbro, K. Grosios, H. A. Lane, P. McSheehy,
J. Mestan, T. Meyer, C. Tang, M. Wartmann, J. Wood and
G. Caravatti, Cancer Res., 2004, 64, 4931–4941; (b)
Y. W. Park, M. N. Younes, S. A. Jasser, O. G. Yigitbasi,
G. Zhou, C. D. Bucana, B. N. Bekele and J. N. Myers, Clin.
Cancer Res., 2005, 11, 1963–1973.
9 S. Ding, T. Y. H. Wu, A. Brinker, E. C. Peters, W. Hur,
N. S. Gray and P. G. Schultz, Proc. Natl. Acad. Sci. U. S. A.,
2003, 100, 7632–7637.
10 (a) S. Tumkevicius, J. Dodonova, K. Kazlauskas,
V. Masevicius, L. Skardziute and S. Jursenas, Tetrahedron
Lett., 2010, 51, 3902–3906; (b) J. Dodonova, L. Skardziute,
K. Kazlauskas, S. Jursenas and S. Tumkevicius,
Tetrahedron, 2012, 68, 329–339.
11 L. Skardziute, K. Kazlauskas, J. Dodonova, J. Bucevicius,
S. Tumkevicius and S. Jursenas, Tetrahedron, 2013, 69,
9566–9572.
12 (a) A. Davoodnia, M. Bakavoli, R. Moloudi, M. Khashi and
N. Tavakoli-Hoseini, Chin. Chem. Lett., 2010, 21, 1–4; (b)
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 35966–35974 | 35973

View Article Online
RSC Advances
Paper
F. Bellina, M. Lessi and C. Manzini, Adv. Synth. Catal., 2014, 18 L.-C. Campeau, M. Parisien, A. Jean and K. Fagnou, J. Am.
356, 17–117. Chem. Soc., 2006, 128, 581–590.
16 I. Cerna, R. Pohl, B. Klepetarova and M. Hocek, J. Org. Chem., 19 D. Lapointe and K. Fagnou, Chem. Lett., 2010, 39, 1118–1126.
2008, 73, 9048–9054.
20 H. Suzuki and T. Nakamura, J. Org. Chem., 1993, 58, 241–244.
17 B. Liegault, D. Lapointe, L. Caron, A. Vlassova and
K. Fagnou, J. Org. Chem., 2009, 74, 1826–1834.
35974 | RSC Adv., 2014, 4, 35966–35974
This journal is © The Royal Society of Chemistry 2014