A Strategy for the Triarylation of Pyrrolopyrimidines by Using Microwave-Promoted Cross-Coupling Reactions

Article abstract of DOI:10.1002/ejoc.201500625

New pyrrolo[2,3-d]pyrimidines that have aryl groups at the 2-, 4-, and 6-positions were prepared by the arylation reaction of 4-chloro-7-methyl-2-(methylthio)-6-phenylpyrrolo[2,3-d]pyrimidine (6) and the corresponding arylboronic acid under Suzuki-Miyaura conditions followed by a second arylation under Liebeskind-Srogl cross-coupling conditions. A parallel study that began with the C-2 chemoselective arylation of 6 under Liebeskind-Srogl conditions followed by a Suzuki-Miyaura coupling at C-4 was carried out, and the results of each route were compared. All of the tranformations were performed under microwave irradiation. Several triarylpyrrolopyrimidines were readily prepared from 4,6-dichloro-2-(methylthio)pyrimidine (2) in excellent yields by using effective cross-coupling reactions. An advantage of this method is its tolerance towards various substituted aryl groups.

Full text of DOI:10.1002/ejoc.201500625

FULL PAPER
DOI: 10.1002/ejoc.201500625
A Strategy for the Triarylation of Pyrrolopyrimidines by Using Microwave-
Promoted Cross-Coupling Reactions
Vanessa Prieur,[a,b] M. Dolors Pujol,* and Gérald Guillaumet*[b]
[a]
Keywords: Nitrogen heterocycles / C–C coupling / Cross-coupling / Amination / Halogenation / Microwave chemistry
New pyrrolo[2,3-d]pyrimidines that have aryl groups at the
parallel study that began with the C-2 chemoselective aryl-
2
-, 4-, and 6-positions were prepared by the arylation reac- ation of 6 under Liebeskind–Srogl conditions followed by a
tion of 4-chloro-7-methyl-2-(methylthio)-6-phenylpyrrolo-
Suzuki–Miyaura coupling at C-4 was carried out, and the re-
sults of each route were compared. All of the tranformations
[
2,3-d]pyrimidine (6) and the corresponding arylboronic acid
under Suzuki–Miyaura conditions followed by a second aryl- were performed under microwave irradiation.
ation under Liebeskind–Srogl cross-coupling conditions. A
Introduction
In previous reports related to the synthesis of pyrrolopyr-
imidines, we employed stepwise arylations at the C-4 and C-
The pyrrolo[2,3-d]pyrimidines also known as deazapur-
ines, because of their structural similarity to natural pur-
ines, are interesting templates for drug discovery programs
in medicinal chemistry and have proved to be valuable
scaffolds in organic chemistry.[ Compounds that contain a
pyrrolopyrimidine nucleus have a variety of biological ef-
[12]
5
positions of 6-aryl-4,6-dihalopyrrolo[2,3-d]pyrimidines,
and more recently, we reported details of a one-pot synthe-
[13]
sis of 4,6-disubstituted pyrrolopyrimidines. The substitu-
[1]
tion of pyrrolopyrimidines is often difficult to control, and
selectivity plays an special role when different substituents
2]
[14]
need to be introduced.
[
3]
[4]
fects including antibacterial, anti-inflammatory, anti-
In this current work, a more selective strategy was devel-
oped to obtain 2,4,6-triarylpyrrolo[2,3-d]pyrimidines from
[
5]
[6]
parasitic, and antitumor properties. In addition to these
pharmaceutical applications, substituted arylpyrimidine, ar-
ylpurine, and deazapurine cores with π-conjugated systems
exhibit interesting photophysical properties.[
4
-chloro-7-methyl-2-(methylthio)-6-phenylpyrrolo[3,2-d]pyr-
imidines. The presence of different leaving groups at the C-
and C-4 positions of the heterocycle allows for highly se-
7]
2
Diaryl-, triaryl-, and tetraarylpurines have been prepared
by intramolecular pyrimidine cyclizations[ and nucleo-
philic substitutions of halogenated purines.[ Consecutive
diarylations at the C-4 and C-2 positions of purines under
lective arylations under Suzuki–Miyaura and Liebeskind–
Srogl conditions.
8]
9]
Pd-catalyzed classical Suzuki–Miyaura conditions have
Results and Discussion
been reported by Hocek et al.,[
9a,9b]
and the same authors
selectively prepared 4,5-diarylpyrrolo[2,3-d]pyrimidines
Retrosynthetic analysis suggests that 2,4,6-trisubstituted
pyrrolo[2,3-d]pyrimidines (IUPAC numbering is used
throughout the manuscript) can be synthesized by a general
approach from monocyclic compounds, which involves an
intramolecular cyclization and double arylations under
cross-coupling conditions. Among several possibilities, we
chose to prepare a versatile key intermediate for the forma-
tion of 2,4,6-triarylated pyrrolopyrimidines from commer-
[
10]
from
4-(phenylthio)-5-iodopyrrolo[2,3-d]pyrimidine.
Tumkevicius et al. obtained 2,4,7-triarylpyrrolo[2,3-d]pyr-
imidines from the corresponding 2,4-dichloropyrrolopyr-
imidines by using a combination of Suzuki–Miyaura cross-
coupling reactions with arylboronic acids and N-arylation
reactions with aryl halides.[
11]
[
a] Laboratori de Química Farmacèutica (Unitat Associada al cially available 4,6-dihydroxy-2-(methylthio)pyrimidine (1).
CSIC), Facultat de Farmàcia, Universitat de Barcelona,
4
,6-Dichloro-2-(methylthio)pyrimidine (2) was obtained
Av. Diagonal 643, 08028 Barcelona, Spain
E-mail: mdpujol@ub.edu
http://www.ub.edu/farmaco/
in 93% yield by applying the procedure of Raboisson et al.,
which involved dichlorination of 4,6-dihydroxy-2-(meth-
ylthio)pyrimidine with POCl and N,N-diethylaniline. 5-
[b] Institut de Chimie Organique et Analytique (ICOA), Université
d’Orléans, UMR CNRS 7311,
[15]
3
Rue de Chartres, BP-6759, 45067 Orléans, France
E-mail: gerald.guillaumet@univ-orleans.fr
www.icoa.fr/en
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500625.
Alkynylpyrimidine 5 was then prepared by the direct and
regioselective substitution of 2 using methylamine followed
by iodination at the C-5 position of 4-chloro-6-(meth-
ylamino)-2-(methylthio)pyrimidine (3) using N-iodosuccin-
Eur. J. Org. Chem. 2015, 6547–6556
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V. Prieur, M. D. Pujol, G. Guillaumet
FULL PAPER
imide (NIS) and then a Sonogashira-type alkynylation by
One approach involves a Pd-catalyzed Suzuki–Miyaura
using phenylacetylene under microwave irradiation. The last cross-coupling reaction of 4-halopyrrolopyrimidines by em-
step involves an intramolecular cyclization of acetylene de- ploying arylboronic acids followed by a Pd(PPh ) /CuTC
3
4
rivative 5 to give 6-arylated deazapurine 6 under conditions catalyzed (TC = thiophene-2-carboxylate) C-2 arylation
[
13]
that we previously established for related compounds.
using arylboronic acid under Liebeskind–Srogl conditions
Our synthetic route towards target 6 included a combina- (Scheme 2, route A). On the other hand, the sequence could
tion of these five steps with an overall yield of 70% be performed in reverse (Scheme 2, route B). Both arylation
(Scheme 1).
reactions were catalyzed by palladium to generate the C–C
bonds, and a set of six substituted phenylboronic acids were
selected for the arylations at the C-2 and C-4 positions
(Tables 1 and 3).
To explore this double arylation process and highlight its
synthetic appeal, new compounds 7a–7f were prepared by
arylation at the C-4 position of pyrrolopyrimidine 6 using
different arylboronic acids under Suzuki–Miyaura condi-
tions and microwave irradiation. According to the results,
neither the position (Table 1, Entries 1–3) nor the nature
(Table 1, Entries 1–4, electron-donating groups, Entry 5,
electron-withdrawing group) of the aryl substituent in the
boronic acid affected the outcome of the reaction (Table 1,
Entries 1–6). In addition, the pyridine substituent also pro-
vided product 7f in excellent yield (Table 1, Entry 6).
By following route A, the next step involved desulfur-
ation of the C-2 position under Liebeskind–Srogl condi-
Scheme 1. Reagents and conditions: (i) POCl
ii) CH NH ·HCl, NEt , iPrOH, reflux, 8 h; (iii) NIS, CH
crowave (MW), 100 °C, 15 min; (iv) Pd(dba) (dba = dibenzylidene-
acetone), P(o-furyl) CuI, phenylacetylene, tetrahydrofuran
THF)/NEt , MW, 100 °C, 30 min; (v) Cs CO , CH CN, MW,
00 °C, 30 min.
3
, N,N-diethylaniline;
(
3
2
3
3
CN, mi-
2
3
,
(
1
3
2
3
3
[
16]
tions.
The optimization of the Liebeskind–Srogl cross-
Considering the attraction of a concise and rapid syn- coupling reaction conditions was performed by using di-
thetic procedure that would allow the preparation of a arylated intermediates 7a and 7d and the corresponding ar-
series of 2,4,6-trisubstituted pyrrolopyrimidines, we were ylboronic acid and by modifying the catalyst and thiophilic
primarily interested in the arylation of heterocyclic interme- metal cocatalyst (Table 2). The solvent and temperature
diate 6. Thus, 4-chloro-7-methyl-2-(methylthio)-6-phenyl- were also varied (Table 2, Entry 4). The desulfurative cou-
pyrrolo[2,3-d]pyrimidine (6) was considered an important pling of nitrogenated aromatic thioethers 7a and 7d with
substructure, which would have applications beyond the the boronic acid proceeded in higher yields by using cop-
current work. Retrosynthetic analysis suggests two general per(I) 3-methylsalicylate (CuMeSal, Table 2, Entries 1 and
approaches for the preparation of 2,4,6-trisubstituted pyr- 5) than by using copper(I) thiophene-2-carboxylate
rolopyrimidines from key building block 6 (Scheme 2, (Table 2, Entries 2–4 and 6). The replacement of a meth-
routes A and B).
ylthio group bonded to an aromatic nucleus generally af-
Scheme 2. Approaches towards the preparation of pyrrolopyrimidine derivatives.
548
6
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A Strategy for the Triarylation of Pyrrolopyrimidines
Table 1. Arylation under Suzuki–Miyaura reaction conditions.[a]
Table 2. Optimization of the Liebeskind–Srogl cross-coupling reac-
tion.
Entry
1
R
Catalyst
Cocatalyst Solvent T [°C] % Yield 7,9
3-CH
7a)
3-CH
7a)
4-CH
7d)
4-CH
7d)
4-CH
7d)
4-CH
7d)
3
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
)
4
CuMeSal THF
100
100
100
93[a]
(9a)
93
–
–
(
2
3
4
5
6
3
3
3
3
3
)
4
CuTC
CuTC
CuTC
THF
THF
(
(9a)
3
O
O
O
O
)
4
64[
b]
36[b]
(7d)
32
(
(9i)
68[
b]
[b]
3
)
4
dioxane 130
(
(9i)
(7d)
–
88[
a]
3
)
4
CuMeSal THF
CuTC THF
100
100
(
(9i)
49[
b]
51[b]
3
2
Pd (dba)
3
,
(
P(o-furyl)
3
(9i)
(7d)
[
a] Yield of isolated and purified compound. [b] Ratio determined
1
by H NMR spectroscopic analysis.
atoms in the heteroaromatic nucleus (in the α positions to
the reaction site) favor the cross-coupling reaction.[
18]
CuTC was less effective than CuMeSal as a cocatalyst
and led to an incomplete reaction, which was confirmed by
the presence of a mixture of triarylated derivative 9 and
starting material 7 (Table 2, Entries 3, 4, and 6). Therefore,
this arylation was best performed under microwave irradia-
tion in THF at 100 °C for 1 h with Pd(PPh ) as the catalyst
3
4
[a] Yield of isolated and purified compound.
and CuMeSal as a cocatalyst. The optimized Liebeskind–
Srogl conditions were then applied to methylthio-substi-
fords the corresponding products in low yields.[17] However tuted deazapurines 7a–7f to explore the scope of this reac-
in this case, the presence of the electronegative nitrogen tion.
Scheme 3. Comparison of both routes (A and B) for the arylation at the C-2 and C-4 positions of pyrrolopyrimidines.
Eur. J. Org. Chem. 2015, 6547–6556
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V. Prieur, M. D. Pujol, G. Guillaumet
FULL PAPER
Table 3. Arylation under Liebeskind–Srogl reaction conditions.[a]
tion (Table 3, Entries 1–4 and 7–11, electron-donating sub-
stituents, Entry 5, electron-withdrawing substituent). Nitro-
genated heterocycles such as a pyridine group also led to
good yields (Table 3, Entry 6). Nevertheless, the position of
the aryl substituent influenced the reaction process, as evi-
denced by the ortho-methylphenyl group of compound 9d
(Table 3, Entry 4). In this case, the yield was lower as a re-
sult of the steric hindrance from the ortho-methyl group.
Finally, the diarylation process was performed by revers-
ing the order of the two steps (Scheme 2, route B). Thus,
the arylation of 6 under the optimized Liebeskind–Srogl
conditions at 100 °C (external temperature) chemoselec-
tively afforded deazapurine 8, which was obtained by dis-
placement of the methylthio group located between two
nitrogen atoms of compound 6 (Scheme 3). A subsequent
arylation at the 4-position under the previously optimized
Suzuki conditions led to triaryl-substituted pyrrolopyrimid-
ine 9a (Scheme 3). Keeping in mind not only the lower yield
of route B (65%) compared with that of route A (80%) but
also the difficulty in isolating the product, this route was
discarded. As with route A, both cocatalysts for the Liebes-
kind reaction were tested in route B, and a better result was
obtained by using CuMeSal (Scheme 3, route B) than with
CuTC (Scheme 3, route BЈ; overall yields of 65 vs. 59%,
respectively).
In this work related to Suzuki–Miyaura and Liebeskind–
[
12,13]
Srogl couplings as well as in previous studies,
we have
used microwave irradiation. The use of microwave irradia-
tion as opposed to conventional heating significantly in-
creases the yield and accelerates the rate of a reaction. In
general, the use of microwave irradiation provides a change
in the thermodynamic properties of the reagents. This is
revealed by a decrease in the Gibbs free energy of activation
for a chemical reaction, which results from the storage of
microwave energy or the energy of vibration for a reagent
[
19]
or substrate and is known as an enthalpy effect.
Conclusions
An efficient and robust route to prepare 2,4,6-triarylated
pyrrolo[2,3-d]pyrimidines has been developed from key in-
termediate 6. Of the two routes explored, the more efficient
involved the Suzuki–Miyaura cross-coupling reaction fol-
lowed by a Liebeskind reaction, which provided higher
yields and had a broader substrate scope than the reverse
process. The process, which began with the arylation at C-
2
under Liebeskind–Srogl conditions, was less effective. The
use of microwave irradiation accelerated the reaction rate to
provide the arylated pyrrolopyrimidines in excellent yields.
A variety of substituents can be selectively introduced at
the C-2 and C-4 positions of pyrrolopyrimidine 6. It is no-
table that substituents can be introduced at these positions
during the last steps of a synthesis, thereby providing an
efficient approach to the construction of a compound li-
[a] Yield of isolated and purified compound.
According to the results, the electronic character of the brary. In the future, this approach will also be used for the
substituents of the arylboronic acids did not affect the reac- preparation of compounds related to pyrrolopyrimidines.
6550
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A Strategy for the Triarylation of Pyrrolopyrimidines
4
diluted with NH Cl (aqueous saturated solution, 15 mL), and the
aqueous phase was extracted with ethyl acetate (3ϫ 20 mL). The
Experimental Section
General Methods: Microwave-assisted reactions were carried out in
a Biotage Initiator microwave synthesis instrument, and the exter-
nal temperature was measured with an IR sensor. The reactions
were monitored by thin layer chromatography using silica gel (60
F254, Merck) plates. Compounds were visualized by UV irradia-
tion. Column chromatography was performed with silica gel 60
combined organic phases were dried with MgSO and filtered
through Celite . Evaporation of the solvent under reduced pressure
gave the crude product, which was purified by silica gel column
chromatography.
4
®
General Procedure D (Cyclization): A solution of the alkyne
(
(
1.0 mmol) and cesium carbonate (1.0 mmol) in acetonitrile
4.5 mL) was transferred into a special microwave tube, and the
(230–400 mesh, 0.040–0.063 mm). Melting points were measured
by using open capillary tubes in a MFB-595010M Gallenkamp ap-
paratus with a digital thermometer. IR spectra were obtained with
mixture was irradiated in a microwave oven at 100 °C for the re-
quired time. The progress of the reaction was monitored by TLC
analysis. After cooling, the solvent was removed in vacuo. Water
1
an FTIR Perkin–Elmer 1600 infrared spectrophotometer. The H
and 13C NMR spectroscopic data were recorded with Bruker
(
20 mL) was added to the mixture, and the crude reaction mixture
was extracted with ethyl acetate (3ϫ 15 mL). The combined or-
ganic phases were washed with Na CO (aqueous saturated solu-
1
3
13
2
7
4
50 MHz ( C NMR, 63 MHz), Varian Gemini-300 ( C NMR,
13
5.5 MHz), Varian Gemini-400 ( C NMR, 100 MHz), and Bruker
1
3
19
2
3
00 MHz ( C NMR, 100 MHz) spectrometers. The F NMR
tion, 15 mL) and brine (15 mL). Evaporation of the solvent under
reduced pressure gave the crude product, which was directly puri-
fied by silica gel column chromatography.
spectroscopic data were recorded with a Bruker (376 MHz, CDCl
spectrometer by using C as the internal standard (δ = 0 ppm).
Chemical shifts are reported in parts per million relative to the
3
)
6 6
F
General Procedure E (Suzuki–Miyaura Coupling at C-4): Under ar-
gon, a mixture of the 4-chloropyrrolo[2,3-d]pyrimidine (1.0 mmol),
the boronic acid (1.05 mmol), sodium carbonate (2.0 mmol), and
tetrakis(triphenylphosphine)palladium (0.02 mmol) in a degassed
central peak of the solvent as the internal standard: CHCl
3
[δ =
1
13
7
.26 ppm ( H NMR)], CDCl
3
[δ = 77.16 ppm ( C NMR)],
1
13
CHD
2
OD [δ = 3.31 ppm ( H NMR)], CD
3
OD [δ = 49.45 ppm ( C
]DMSO [δ =
9.51 ppm ( C NMR)]. The following abbreviations are used to
1
NMR)], [D
3
5
1
]DMSO [δ = 2.49 ( H NMR)], and [D
6
3
2
solvent mixture of 1,2-dimethoxyethane (DME, 3.8 mL) and H O
(
0.6 mL) was transferred into a special microwave tube and irradi-
describe the multiplicity of the signal in the proton spectra: s (sing-
let), d (doublet), t (triplet), q (quadruplet), and m (multiplet). Cou-
pling constants are reported in Hertz. High resolution mass spectra
were performed on a Maxis Bruker 4G by using the ICOA platform
at the University of Orléans (France) or on a LC/MSD-TOF (2006,
Agilent technologies) at the “Center of mass spectrometry” at the
University of Barcelona (Spain). All reagents were of high quality
or purified before use. Organic solvents were of analytical grade or
purified by standard procedures.
ated in a microwave oven at 100 °C for 60–90 min. The progress of
the reaction was monitored by TLC analysis. After cooling, the
mixture was diluted with a mixture of brine and water (1:1, 20 mL),
and the aqueous solution was extracted with ethyl acetate (3ϫ
20 mL). The evaporation of the solvent under reduced pressure
gave the crude product, which was purified by silica gel column
chromatography.
General Procedure F (Liebeskind–Srogl Coupling at C-2): Under
argon, a mixture of 4,6-diaryl-2-(methylthio)pyrrolo[2,3-d]pyrimid-
ine (1.0 mmol), the boronic acid (1.5 mmol), CuMeSal (3.0 mmol),
and tetrakis(triphenylphosphine)palladium (0.1 mmol) in degassed
THF (8.0 mL) was transferred into a special microwave tube and
irradiated in a microwave oven at 100 °C for 60 min. The progress
of the reaction was monitored by TLC analysis. After cooling, the
mixture was diluted with dichloromethane (20 mL), and the re-
General Procedure A (Amination): To a solution of the dichloropyr-
imidine (1.0 mmol) in 2-propanol (1.0 mL) were added triethyl-
amine (1.2 mmol) and the amine (1.2 mmol). The reaction was
stirred and heated at the reflux temperature of 2-propanol (or of
the amine if it is lower) until there was complete consumption of
the starting material as determined by TLC analysis. After cooling,
the solvent was removed in vacuo. Water (15 mL) was added, and
the mixture was then extracted with ethyl acetate (3ϫ 15 mL). The
2 3
sulting mixture was washed with a saturated solution of Na CO
until the aqueous washings were completely colorless. Evaporation
of the solvent under reduced pressure gave the crude product,
which was purified by silica gel column chromatography.
4
combined organic layers were washed with NH Cl (10 mL). Evapo-
ration of the solvent under reduced pressure gave the crude prod-
uct, which was purified by silica gel column chromatography.
4
,6-Dichloro-2-(methylthio)pyrimidine (2): 2-(Methylthio)pyrimidin-
General Procedure B (Pyrimidine Iodination): A solution of the N-
methylpyrimidine-4-amine (1.0 mmol) and NIS (3.0 mmol) in
acetonitrile (2 mL) was transferred into a special microwave tube,
and the mixture was irradiated in a microwave oven at 100 °C for
4,6-diol (2.00 g, 12.6 mmol) and N,N-diethylaniline (3.65 mL) were
added slowly to phosphorus oxychloride (23.3 mL), which was
cooled on ice. The mixture was slowly warmed to reflux, heated at
this temperature for 2.5 h, and then evaporated. The resulting mix-
ture was added to crushed ice and then extracted with ethyl acetate
1
5 min. The progress of the reaction was monitored by TLC analy-
sis. After cooling, the solvent was removed. Dichloromethane
20 mL) was added, and the organic layer was washed with
Na (aqueous saturated solution, 2ϫ 16 mL) and NaOH
10%, 2ϫ 16 mL). Evaporation of the solvent under reduced pres-
(
3ϫ). The combined organic layers were washed with water (3ϫ)
(
and brine (1ϫ) and then concentrated. The crude product was puri-
fied by silica gel column chromatography (petroleum ether/di-
chloromethane, 9:1) to afford 2 (2.30 g, 11.8 mmol, 93% yield) as
colorless crystals; m.p. 42–43 °C (pentane). IR [attenuated total re-
flectance (ATR) diamond]: ν˜ = 2956, 2928, 2855, 1539, 1532, 1509,
2 2 3
S O
(
sure gave the crude product, which was purified by silica gel column
chromatography or recrystallization.
–
1
1
1
469, 1358, 1272, 1215, 1099, 843, 825, 80 cm . H NMR
400 MHz, CDCl ): δ = 2.57 (s, 3 H, SCH ), 6.89 (s, 1 H, 5-H) ppm.
C NMR (100 MHz, CDCl ): δ = 13.9 (CH ), 115.6 (CH), 161.2
2 Cq), 174.1 (Cq) ppm. HRMS (ESI): calcd. for C Cl S [M
General Procedure C (Sonogashira Coupling): A mixture of the 5-
(
3
3
iodopyrimidine (1.0 mmol), the alkyne (2.0 mmol), Pd(dba)
2
1
3
3
3
(
(
0.03 mmol), tri(2-furyl)phosphine (0.06 mmol), and CuI
0.04 mmol) in dry THF (1 mL) and dry triethylamine (3.5 mL)
(
5
H
5
2 2
N
+
+
H] 194.9545; found 194.9539.
was transferred into a special microwave tube and irradiated in a
microwave oven at 100 °C for 30 min. The progress of the reaction
was monitored by TLC analysis. After cooling, the mixture was
6-Chloro-N-methyl-2-(methylthio)pyrimidin-4-amine (3): The reac-
tion was carried out by following general procedure A and starting
Eur. J. Org. Chem. 2015, 6547–6556
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6551

V. Prieur, M. D. Pujol, G. Guillaumet
FULL PAPER
from 4,6-dichloro-2-(methylthio)pyrimidine (2, 2.30 g, 11.8 mmol)
and MeNH ·HCl (955 mg, 14.1 mmol). The reaction was stirred
2
and heated at the reflux temperature of 2-propanol. The crude
product was purified by silica gel column chromatography (di-
chloromethane/ethyl acetate, 6:4) to afford 3 (1.97 g, 10.4 mmol,
chromatography (petroleum ether/dichloromethane, 7:3) to afford
7a (308 mg, 0.890 mmol, 86% yield) as a yellow solid; m.p. 152–
155 °C (pentane). IR (ATR diamond): ν˜ = 2924, 1557, 1485, 1358,
–
1
1
1333, 1261, 1147, 962, 744, 700 (m) cm . H NMR (400 MHz,
CDCl ): δ = 2.47 (s, 3 H, CH ), 2.74 (s, 3 H, SCH ), 3.84 (s, 3 H,
NCH ), 6.78 (s, 1 H, 5-H), 7.31 (d, J = 7.5 Hz, 1 H, H-Ar), 7.41
3
3
3
88% yield) as an off-white solid; m.p. 129–131 °C (ethyl acetate).
3
IR (ATR diamond): ν˜ = 3261, 3138, 2928, 1564, 1493, 1423, 1360,
(t, J = 7.7 Hz, 1 H, H-Ar), 7.44–7.59 (m, 5 H, H-Ar), 7.96 (d, J =
7.8 Hz, 1 H, H-Ar), 7.99 (s, 1 H, H-Ar) ppm. C NMR (100 MHz,
CDCl ): δ = 14.7 (CH ), 21.7 (CH ), 30.1 (CH ), 100.2 (CH), 112.8
3 3 3 3
–1
1
13
1
273, 1224, 1117, 965, 806, 677 cm . H NMR (400 MHz, CDCl
δ = 2.48 (s, 3 H, SCH ), 2.93 (s, 3 H, NCH ), 5.40 (s, 1 H, NH),
.03 (s, 1 H, 5-H) ppm. 13C NMR (100 MHz, CDCl
): δ = 14.2 (Cq), 126.2 (CH), 128.6 (CH), 128.8 (CH), 128.9 (2 CH), 129.2 (2
CH ), 28.4 (CH ), 96.4 (CH), 159.4 (Cq), 163.6 (Cq), 172.1 CH), 129.6 (CH), 130.9 (CH), 131.8 (Cq), 138.2 (Cq), 138.5 (Cq),
Cq) ppm. HRMS (ESI): calcd. for C
3
):
3
3
6
(
(
3
3
3
+
6
H
9
ClN
3
S [M + H] 190.0200;
141.5 (Cq), 154.7 (Cq), 157.1 (Cq), 164.0 (Cq) ppm. HRMS (ESI):
calcd. for C21
S [M + H]+ 346.1372; found 346.1370.
found 190.0197.
20 3
H N
6-Chloro-5-iodo-N-methyl-2-(methylthio)pyrimidin-4-amine (4): The
7
-Methyl-2-(methylthio)-6-phenyl-4-(p-tolyl)-7H-pyrrolo[2,3-d]pyr-
reaction was carried out by following general procedure B and
starting from pyrimidine 3 (1.90 g, 10.0 mmol). The crude product
was purified by silica gel column chromatography (petroleum ether/
dichloromethane, 5:5) to afford 4 (2.89 g, 9.17 mmol, 91% yield) as
a white solid; m.p. 142–144 °C (ethyl acetate). IR (ATR diamond):
ν˜ = 3397, 3378, 2919, 1564, 1526, 1483, 1410, 1375, 1321, 1254,
imidine (7b): The reaction was carried out by following general pro-
cedure E and starting from 4-chloropyrrolopyrimidine 6 (50.0 mg,
0
.173 mmol) and 4-tolylboronic acid (24.6 mg, 0.181 mmol). The
crude product was purified by silica gel column chromatography
petroleum ether/dichloromethane, 5:5) to afford 7b (55.0 mg,
.159 mmol, 92% yield) as a pale yellow solid; m.p. 106–108 °C
pentane). IR (ATR diamond): ν˜ = 2924, 1553, 1487, 1362, 1334,
(
0
(
–1 1
1
221, 1135, 1096, 992, 931, 825, 750 cm . H NMR (400 MHz,
CDCl ): δ = 2.51 (s, 3 H, SCH ), 3.05 (s, J = 4.9 Hz, 3 H, NCH ),
.55 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl
): δ = 14.5
CH ), 29.4 (CH ), 72.9 (Cq), 161.6 (Cq), 162.0 (Cq), 171.7
Cq) ppm. HRMS (ESI): calcd. for C ClIN
S [M + H]+
–1 1
3
3
3
1
262, 1179, 1147, 954, 835, 750, 701 cm . H NMR (400 MHz,
): δ = 2.44 (s, 3 H, CH ), 2.74 (s, 3 H, SCH ), 3.83 (s, 3 H,
), 6.78 (s, 1 H, 5-H), 7.33 (d, J = 7.9 Hz, 2 H, H-Ar), 7.42–
.52 (m, 3 H, H-Ar), 7.53–7.58 (m, 2 H, H-Ar), 8.10 (d, J = 7.9 Hz,
5
(
(
3
CDCl
NCH
3
3
3
3
3
3
6
H
8
3
7
2
2
315.9167; found 315.9162.
13
H, H-Ar) ppm. C NMR (100 MHz, CDCl
3 3
): δ = 14.6 (CH ),
1.6 (CH ), 30.1 (CH ), 100.1 (CH), 112.6 (Cq), 128.7 (CH), 128.8
3
3
6
-Chloro-N-methyl-2-(methylthio)-5-(phenylethynyl)pyrimidin-4-
(
1
(
2 CH), 128.9 (2 CH), 129.1 (2 CH), 129.5 (2 CH), 131.7 (Cq),
35.5 (Cq), 140.3 (Cq), 141.4 (Cq), 154.7 (Cq), 156.7 (Cq), 163.9
Cq) ppm. HRMS (ESI): calcd. for C21H N S [M + H] 346.1372;
20 3
amine (5): The reaction was carried out by following general pro-
cedure C amd starting from iodinated pyrimidine 4 (2.22 g,
+
7.04 mmol) and phenylacetylene (1.54 mL, 14.1 mmol). The crude
found 346.1371.
product was purified by silica gel column chromatography (petro-
leum ether/dichloromethane, 6:4) to afford 5 (1.97 mg, 6.80 mmol,
7
-Methyl-2-(methylthio)-6-phenyl-4-(o-tolyl)-7H-pyrrolo[2,3-d]pyr-
97% yield) as a yellow solid; m.p. 131–133 °C (pentane). IR (ATR
imidine (7c): The reaction was carried out by following general pro-
cedure E and starting from 4-chloropyrrolopyrimidine 6 (50.0 mg,
diamond): ν˜ = 3342, 2932, 1553, 1488, 1366, 1220, 1082, 938, 853,
–
1 1
8
11, 751, 687 cm . H NMR (400 MHz, CDCl
SCH ), 3.11 (d, J = 5.0 Hz, 3 H, NCH ), 5.67 (s, 1 H, NH), 7.34–
.41 (m, 3 H, H-Ar), 7.50–7.57 (m, 2 H, H-Ar) ppm. 13C NMR
100 MHz, CDCl ): δ = 14.4 (CH ), 28.4 (CH ), 80.2 (Cq), 96.1
Cq), 101.4 (Cq), 122.4 (Cq), 128.6 (2 CH), 129.1 (CH), 131.6 (2
3
): δ = 2.55 (s, 3 H,
0
.173 mmol) and 2-tolylboronic acid (24.6 mg, 0.181 mmol). The
crude product was purified by silica gel column chromatography
petroleum ether/dichloromethane, 2:8) to afford 7c (58.6 mg,
.170 mmol, 98 % yield) as a dark yellow solid; m.p. 74–76 °C
pentane). IR (ATR diamond): ν˜ = 2922, 2359, 1557, 1489, 1357,
3
3
7
(
(
(
0
(
3
3
3
CH), 158.7 (Cq), 162.1 (Cq), 170.8 (Cq) ppm. HRMS (ESI): calcd.
–
1 1
1
332, 1254, 1184, 1142, 958, 750, 697 cm . H NMR (400 MHz,
): δ = 2.42 (s, 3 H, CH ), 2.70 (s, 3 H, SCH ), 3.85 (s, 3 H,
), 6.39 (s, 1 H, 5-H), 7.28–7.37 (m, 3 H, H-Ar), 7.42–7.55
+
for C14
3
H13ClN S [M + H] 290.0513; found 290.0510.
CDCl
NCH
3
3
3
4
-Chloro-7-methyl-2-(methylthio)-6-phenyl-7H-pyrrolo[2,3-d]pyr-
3
1
3
(
(
1
1
m, 6 H, H-Ar) ppm. C NMR (100 MHz, CDCl
CH ), 20.5 (CH ), 30.1 (CH ), 100.1 (CH), 114.6 (Cq), 125.7 (CH),
28.8 (CH), 128.9 (2 CH), 129.1 (2 CH), 129.2 (CH), 130.0 (CH),
31.2 (CH), 131.7 (Cq), 136.9 (Cq), 137.3 (Cq), 141.4 (Cq), 154.2
3
): δ = 14.6
imidine (6): The reaction was carried out by following general pro-
cedure D and starting from alkyne 5 (1.87 g, 6.45 mmol). Micro-
wave irradiation was applied for 30 min. The crude product was
purified by silica gel column chromatography (petroleum ether/
dichloromethane, 5:5) to afford 6 (1.81 mg, 6.25 mmol, 97% yield)
as an off-white solid; m.p. 94–96 °C (pentane). IR (ATR diamond):
ν˜ = 2930, 1587, 1531, 1486, 1375, 1236, 1179, 1127, 960, 866, 748,
3
3
3
(
Cq), 159.5 (Cq), 163.8 (Cq) ppm. HRMS (ESI): calcd. for
S [M + H]+ 346.1372; found 346.1372.
21 20 3
C H N
–
1
1
4-(4-Methoxyphenyl)-7-methyl-2-(methylthio)-6-phenyl-7H-
pyrrolo[2,3-d]pyrimidine (7d): The reaction was carried out by fol-
lowing general procedure E and starting from 4-chloropyrrolopyr-
imidine 6 (50.0 mg, 0.173 mmol) and (4-methoxyphenyl)boronic
acid (27.5 mg, 0.181 mmol). The crude product was purified by sil-
ica gel column chromatography (petroleum ether/dichloromethane,
6
3
98 cm . H NMR (400 MHz, CDCl
.79 (s, 3 H, NCH ), 6.53 (s, 1 H, 5-H), 7.46–7.54 (m, 5 H, H-
): δ = 14.6 (SCH ), 30.4
), 98.9 (CH), 114.2 (Cq), 129.0 (2 CH), 129.1 (CH), 129.2
3 3
): δ = 2.66 (s, 3 H, SCH ),
3
1
3
Ar) ppm. C NMR (100 MHz, CDCl
3
3
(
(
(
NCH
3
2 CH), 131.1 (Cq), 141.8 (Cq), 150.6 (Cq), 151.4 (Cq), 152.7
Cq) ppm. HRMS (ESI): calcd. for C14
S [M + H]+
H13ClN
3
2
:8) to afford 7d (62.0 mg, 0.172 mmol, 99% yield) as a yellow so-
290.0513; found 290.0511.
lid; m.p. 55–57 °C (pentane). IR (ATR diamond): ν˜ = 2924, 1553,
–
1 1
7
-Methyl-2-(methylthio)-6-phenyl-4-(m-tolyl)-7H-pyrrolo[2,3-d]-
1509, 1488, 1336, 1250, 1171, 1029, 956, 838, 748, 699 cm .
NMR (400 MHz, CDCl ): δ = 2.73 (s, 3 H, SCH ), 3.82 (s, 3 H,
OCH ), 3.88 (s, 3 H, NCH ), 6.77 (s, 1 H, 5-H), 7.04 (d, J = 8.3 Hz,
2 H, H-Ar), 7.42–7.58 (m, 5 H, H-Ar), 8.18 (d, J = 8.3 Hz, 2 H,
H
pyrimidine (7a): The reaction was carried out by following general
procedure E and starting from the 4-chloropyrrolopyrimidine 6
3
3
3
3
(
300 mg, 1.04 mmol) and 3-tolylboronic acid (147.8 mg,
.09 mmol). The crude product was purified by silica gel column
1
3
1
6
3 3
H-Ar) ppm. C NMR (100 MHz, CDCl ): δ = 14.6 (CH ), 30.1
552
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6547–6556

A Strategy for the Triarylation of Pyrrolopyrimidines
(
(
(
(
CH
3 3
), 55.5 (CH ), 100.1 (CH), 112.2 (Cq), 114.1 (2 CH), 128.7 (33.0 mg, 0.22 mmol). The crude product was purified by silica gel
CH), 128.8 (2 CH), 129.1 (2 CH), 130.5 (2 CH), 130.8 (Cq), 131.7 column chromatography (petroleum ether/dichloromethane, 5:5) to
Cq), 141.2 (Cq), 154.7 (Cq), 156.3 (Cq), 161.3 (Cq), 163.8
Cq) ppm. HRMS (ESI): calcd. for C21
OS [M + H]+
afford 9a (54.7 mg, 0.14 mmol, 93% yield) as a pale yellow solid;
m.p. 138–140 °C (pentane). IR (ATR diamond): ν˜ = 3053, 2915,
20 3
H N
–
1 1
3
62.1322; found 362.1319.
1550, 1512, 1487, 1374, 1299, 1243, 1166, 1031, 748, 695 cm . H
NMR (400 MHz, CDCl ): δ = 2.51 (s, 3 H, CH ), 3.91 (s, 3 H,
OCH ), 3.95 (s, 3 H, NCH ), 6.86 (s, 1 H, 5-H), 7.05 (d, J = 8.2 Hz,
H, H-Ar), 7.33 (d, J = 7.0 Hz, 1 H, H-Ar), 7.44–7.61 (m, 6 H,
H-Ar), 8.16–8.04 (m, 2 H, H-Ar), 8.67 (d, J = 8.2 Hz, 2 H, H-
3
3
7
7
-Methyl-2-(methylthio)-6-phenyl-4-[4-(trifluoromethyl)phenyl]-
H-pyrrolo[2,3-d]pyrimidine (7e): The reaction was carried out by
3
3
2
following general procedure E and starting from the 4-chloropyr-
rolopyrimidine 6 (50.0 mg, 0.173 mmol) and [4-(trifluoromethyl)-
phenyl]boronic acid (34.4 mg, 0.181 mmol). The crude product was
purified by silica gel column chromatography (petroleum ether/
dichloromethane, 6:4) to afford 7e (64.7 mg, 0.162 mmol, 94%
yield) as a light green solid; m.p. 131–133 °C (pentane). IR (ATR
diamond): ν˜ = 2923, 1557, 1489, 1358, 1331, 1254, 1184, 1142, 958,
1
3
Ar) ppm. C NMR (100 MHz, CDCl
3
): δ = 21.8 (CH
3
), 30.1
(
(
(
(
CH ), 55.5 (CH ), 100.2 (CH), 113.8 (2 CH), 114.0 (Cq), 126.3
CH), 128.6 (CH), 128.8 (CH), 128.9 (2 CH), 129.2 (2 CH), 129.7
2 CH), 129.8 (CH), 130.7 (CH), 132.0 (Cq), 132.2 (Cq), 138.5
3 3
Cq), 139.1 (Cq), 142.6 (Cq), 154.8 (Cq), 156.7 (Cq), 157.6 (Cq),
+
1
24 3
61.1 (Cq) ppm. HRMS (ESI): calcd. for C27H N O [M + H]
–1 1
7
58, 750, 697 cm . H NMR (400 MHz, CDCl
SCH ), 3.84 (s, 3 H, NCH ), 6.74 (s, 1 H, 5-H), 7.46–7.58 (m, 5 H,
H-Ar), 7.77 (d, J = 8.1 Hz, 2 H, H-Ar), 8.27 (d, J = 8.1 Hz, 2 H,
H-Ar) ppm. 13C NMR (100 MHz, CDCl
): δ = 14.6 (CH ), 30.1
CH ), 99.5 (CH), 113.0 (Cq), 124.2 (q, J = 272 Hz, Cq), 125.7 (q,
J = 4 Hz, 2 CH), 128.9 (2 CH), 129.0 (CH), 129.1 (2 CH), 129.3
3
): δ = 2.73 (s, 3 H,
406.1914; found 406.1910.
3
3
7
-Methyl-6-phenyl-4-(m-tolyl)-2-(p-tolyl)-7H-pyrrolo[2,3-d]pyr-
3
3
imidine (9b): The reaction was carried out by following general pro-
cedure F and starting from 4-arylpyrrolopyrimidine 7a (50.0 mg,
(
3
0
.145 mmol) and 4-tolylboronic acid (29.5 mg, 0.217 mmol). The
crude product was purified by silica gel column chromatography
petroleum ether/dichloromethane, 7:3) to afford 9b (56.1 mg,
.144 mmol, 99% yield) as a yellow solid; m.p. 153–154 °C (pent-
ane). IR (ATR diamond): ν˜ = 3052, 2916, 2855, 1552, 1488, 1374,
(
(
(
2 CH), 131.4 (Cq), 131.5 (Cq), 131.7 (q, J = 32 Hz, Cq), 141.6
Cq), 142.4 (Cq), 154.9 (Cq), 164.1 (Cq) ppm. 1 F NMR
9
(
0
376 MHz, CDCl
3 3
): δ = –62.66 (CF ) ppm. HRMS (ESI): calcd.
+
for C21
17 3 3
H F N
S [M + H] 400.1090; found 400.1088.
–
1 1
1304, 1262, 1168, 834, 766, 697 cm . H NMR (400 MHz, CDCl
3
):
),
7
-Methyl-2-(methylthio)-6-phenyl-4-(pyridin-3-yl)-7H-pyrrol[2,3-
δ = 2.48 (s, 3 H, CH ), 2.54 (s, 3 H, CH ), 3.96 (s, 3 H, NCH
3
3
3
d]pyrimidine (7f): The reaction was carried out by following general
procedure E and starting from 4-chloropyrrolopyrimidine 6
6
4
8
.88 (s, 1 H, 5-H), 7.35 (d, J = 7.6 Hz, 3 H, H-Ar), 7.45–7.55 (m,
H, H-Ar), 7.58–7.63 (m, 2 H, H-Ar), 8.09–8.18 (m, 2 H, H-Ar),
(
0
50.0 mg, 0.173 mmol) and (3-pyridinyl)boronic acid (22.3 mg,
.181 mmol). The crude product was purified by silica gel column
chromatography (dichloromethane/ethyl acetate, 6:4) to afford 7f
54.5 mg, 0.169 mmol, 98 % yield) as a yellow solid; m.p. 137–
1
3
.64 (d, J = 7.8 Hz, 2 H, H-Ar) ppm. C NMR (100 MHz,
): δ = 21.6 (CH ), 21.8 (CH ), 30.0 (CH ), 100.2 (CH), 114.2
Cq), 126.3 (CH), 128.1 (2 CH), 128.6 (CH), 128.8 (CH), 128.9 (2
CDCl
(
3
3
3
3
(
CH), 129.1 (2 CH), 129.2 (2 CH), 129.6 (CH), 130.7 (CH), 131.9
(Cq), 136.7 (Cq), 138.4 (Cq), 139.0 (Cq), 139.5 (Cq), 142.8 (Cq),
1
1
(
6
1
39 °C (pentane). IR (ATR diamond): ν˜ = 2997, 1542, 1487, 1359,
–
1 1
323, 1268, 1193, 1154, 1024, 956, 744, 702 cm
): δ = 2.73 (s, 3 H, SCH ), 3.85 (s, 3 H, NCH
.77 (s, 1 H, 5-H), 7.44–7.57 (m, 6 H, H-Ar), 8.48 (d, J = 7.8 Hz,
.
H NMR
1
54.7 (Cq), 156.6 (Cq), 157.7 (Cq) ppm. HRMS (ESI): calcd. for
400 MHz, CDCl
3
3
3
),
[M + H]+ 390.1965; found 390.1963.
27 24 3
C H N
1
3
H, H-Ar), 8.72 (s, 1 H, H-Ar), 9.41 (s, 1 H, H-Ar) ppm.
): δ = 14.7 (CH ), 30.2 (CH ), 99.4 (CH),
12.9 (Cq), 123.4 (CH), 129.0 (2 CH), 129.1 (CH), 129.2 (2 CH),
31.4 (Cq), 134.1 (Cq), 136.2 (CH), 142.4 (Cq), 150.1 (CH), 150.9
C
7
-Methyl-6-phenyl-2,4-di-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine (9c):
NMR (100 MHz, CDCl
1
1
3
3
3
The reaction was carried out by following general procedure F and
starting from 4-arylpyrrolopyrimidine 7a (50.0 mg, 0.145 mmol)
and 3-tolylboronic acid (29.5 mg, 0.217 mmol). The crude product
was purified by silica gel column chromatography (petroleum ether/
dichloromethane, 7:3) to afford 9c (50.3 mg, 0.129 mmol, 89%
yield) as a pale yellow solid; m.p. 154–156 °C (pentane). IR (ATR
diamond): ν˜ = 3047, 2917, 1552, 1488, 1394, 1373, 1261, 920, 861,
(
CH), 153.8 (Cq), 154.8 (Cq), 164.3 (Cq) ppm. HRMS (ESI): calcd.
+
for C19
17 4
H N S [M + H] 333.1168; found 333.1167.
4
-Chloro-2-(4-methoxyphenyl)-7-methyl-6-phenyl-7H-pyrrolo[2,3-
d]pyrimidine (8a): The reaction was carried out by following general
procedure F and starting from the 4-chloropyrrolopyrimidine 6
–
1 1
7
68, 696 cm . H NMR (400 MHz, CDCl
CH ), 3.98 (s, 3 H, NCH ), 6.88 (s, 1 H, 5-H), 7.28 (d, J = 7.7 Hz,
H, H-Ar), 7.34 (d, J = 7.6 Hz, 1 H, H-Ar), 7.40–7.55 (m, 5 H,
H-Ar), 7.58–7.63 (m, 2 H, H-Ar), 8.06–8.16 (m, 2 H, H-Ar), 8.49–
3
): δ = 2.52 (s, 6 H, 2
(
(
50.0 mg, 0.173 mmol) and (4-methoxyphenyl)boronic acid
39.3 mg, 0.259 mmol). The crude product was purified by silica gel
3
3
1
column chromatography (petroleum ether/dichloromethane, 2:8) to
afford 8 (48.9 mg, 0.140 mmol, 81% yield) as a beige solid; m.p.
1
1
1
3
8.56 (m, 2 H, H-Ar) ppm. C NMR (100 MHz, CDCl
3
): δ = 21.8
(
2 CH ), 30.1 (CH ), 100.2 (CH), 114.4 (Cq), 125.4 (CH), 126.3
3
3
25–126 °C (pentane). IR (ATR diamond): ν˜ = 2925, 1588, 1530,
–1
1
(CH), 128.4 (CH), 128.6 (CH), 128.7 (CH), 128.8 (CH), 128.9 (2
CH), 129.2 (2 CH), 129.7 (CH), 130.4 (CH), 130.8 (CH), 131.9
463, 1394, 1244, 1168, 1129, 1022, 954, 761, 743 cm . H NMR
): δ = 3.88 (s, 3 H, OCH ), 3.89 (s, 3 H, NCH ),
.59 (s, 1 H, 5-H), 7.00 (d, J = 8.4 Hz, 2 H, H-Ar), 7.45–7.58 (m,
(400 MHz, CDCl
3
3
3
(
Cq), 138.0 (Cq), 138.5 (Cq), 139.0 (Cq), 139.3 (Cq), 143.0 (Cq),
154.7 (Cq), 156.8 (Cq), 157.8 (Cq) ppm. HRMS (ESI): calcd. for
[M + H]+ 390.1964; found 390.1966.
6
5
H, H-Ar), 8.50 (d, J = 8.4 Hz, 2 H, H-Ar) ppm. 1 C NMR
3
(100 MHz, CDCl
3
): δ = 30.4 (NCH ), 55.5 (OCH ), 98.9 (CH),
3
3
27 24 3
C H N
1
1
13.9 (2 CH), 115.5 (Cq), 129.0 (2 CH), 129.1 (CH), 129.2 (2 CH),
29.8 (2 CH), 130.5 (Cq), 131.3 (Cq), 142.9 (Cq), 151.5 (Cq), 153.8
7
-Methyl-6-phenyl-4-(m-tolyl)-2-(o-tolyl)-7H-pyrrolo[2,3-d]pyr-
imidine (9d): The reaction was carried out by following general pro-
cedure F and starting from 4-arylpyrrolopyrimidine 7a (50.0 mg,
0
(
Cq), 157.6 (Cq), 161.5 (Cq) ppm. HRMS (ESI): calcd. for
+
20 3
C H17ClN O [M + H] 350.1055; found 350.1052.
.145 mmol) and 2-tolylboronic acid (29.5 mg, 0.217 mmol). The
-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(m-tolyl)-7H-pyrrolo- crude product was purified by silica gel column chromatography
2,3-d]pyrimidine (9a): The reaction was carried out by following (petroleum ether/dichloromethane, 7:3) to afford 9d (34.0 mg,
2
[
–
2
general procedure F and starting from the 4-arylpyrrolopyrimidine
7
8.73 ϫ 10 mmol, 60 % yield) as a white solid; m.p. 114–116 °C
(pentane). IR (ATR diamond): ν˜ = 3056, 2918, 1549, 1488, 1396,
a (50 mg, 0.15 mmol) and (4-methoxyphenyl)boronic acid
Eur. J. Org. Chem. 2015, 6547–6556
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6553

V. Prieur, M. D. Pujol, G. Guillaumet
FULL PAPER
1
–1 1
375, 1260, 745, 696 cm . H NMR (400 MHz, CDCl
s, 3 H, CH ), 2.74 (s, 3 H, CH ), 3.94 (s, 3 H, NCH
H, 5-H), 7.30–7.38 (m, 4 H, H-Ar), 7.42–7.56 (m, 4 H, H-Ar), 7.59– CDCl
.65 (m, 2 H, H-Ar), 8.02–8.12 (m, 3 H, H-Ar) ppm. 13C NMR (Cq), 113.8 (2 CH), 128.7 (CH), 128.8 (2 CH), 129.0 (2 CH), 129.1
100 MHz, CDCl ): δ = 21.8 (2 CH ), 30.2 (CH ), 100.0 (CH), (2 CH), 129.5 (2 CH), 129.6 (2 CH), 132.0 (Cq), 132.2 (Cq), 136.3
13.7 (Cq), 126.0 (CH), 126.3 (CH), 128.7 (CH), 128.9 (2 CH), (Cq), 140.0 (Cq), 142.5 (Cq), 154.8 (Cq), 156.4 (Cq), 157.5 (Cq),
3
): δ = 2.49 7.59 (d, J = 7.2 Hz, 2 H, H-Ar), 8.24 (d, J = 7.8 Hz, 2 H, H-Ar),
1
3
(
3
3
3
), 6.91 (s, 1 8.68 (d, J = 8.5 Hz, 2 H, H-Ar) ppm. C NMR (100 MHz,
): δ = 21.6 (CH ), 30.1 (CH ), 55.5 (CH ), 100.2 (CH), 113.7
3
3
3
3
7
(
3
3
3
1
1
1
+
29.3 (3 CH), 129.7 (2 CH), 130.7 (CH), 130.9 (CH), 131.3 (CH),
31.9 (Cq), 137.4 (Cq), 138.5 (Cq), 138.9 (Cq), 139.8 (Cq), 143.0 406.1914; found 406.1910.
24 3
161.1 (Cq) ppm. HRMS (ESI): calcd. for C27H N O [M + H]
(
Cq), 154.4 (Cq), 156.6 (Cq), 160.3 (Cq) ppm. HRMS (ESI): calcd.
+
for C27
H
24
N
3
[M + H] 390.1965; found 390.1963.
2-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(o-tolyl)-7H-pyrrolo-
2,3-d]pyrimidine (9h): The reaction was carried out by following
general procedure F and starting from 4-arylpyrrolopyrimidine 7c
50 mg, 0.145 mmol) and (4-methoxyphenyl)boronic acid (33.0 mg,
.217 mmol). The crude product was purified by silica gel column
chromatography (petroleum ether/dichloromethane, 2:8) to afford
[
7
-Methyl-6-phenyl-4-(m-tolyl)-2-[4-(trifluoromethyl)phenyl]-7H-
pyrrolo[2,3-d]pyrimidine (9e): The reaction was carried out by fol-
lowing general procedure F and starting from 4-arylpyrrolopyrim-
idine 7a (50.0 mg, 0.145 mmol) and [4-(trifluoromethyl)phenyl]-
boronic acid (41.2 mg, 0.217 mmol). The crude product was puri-
fied by silica gel column chromatography (petroleum ether/di-
chloromethane, 7:3) to afford 9e (61.1 mg, 0.138 mmol, 95% yield)
as a white solid; m.p. 137–139 °C (pentane). IR (ATR diamond): ν˜
(
0
9
1
1
h (55.8 mg, 0.138 mmol, 95% yield) as a white solid; m.p. 128–
30 °C (pentane). IR (ATR diamond): ν˜ = 3057, 2929, 1560, 1376,
–1
1
300, 1246, 1160, 1031, 842, 759, 698 cm . H NMR (400 MHz,
): δ = 2.55 (s, 3 H, CH ), 3.90 (s, 3 H, OCH ), 3.97 (s, 3 H,
), 6.51 (s, 1 H, 5-H), 7.03 (d, J = 8.6 Hz, 2 H, H-Ar), 7.32–
.37 (m, 1 H, H-Ar), 7.37–7.42 (m, 2 H, H-Ar), 7.43–7.52 (m, 3 H,
CDCl
NCH
7
3
3
3
–
1 1
=
2917, 1551, 1318, 1165, 1119, 1063, 858, 769, 747, 697 cm . H
NMR (400 MHz, CDCl ): δ = 2.53 (s, 3 H, CH ), 3.95 (s, 3 H,
NCH ), 6.89 (s, 1 H, 5-H), 7.32–7.39 (m, 1 H, H-Ar), 7.45–7.62
m, 6 H, H-Ar), 7.77 (d, J = 8.0 Hz, 2 H, H-Ar), 8.06–8.15 (m, 2 H,
3
3
3
3
H-Ar), 7.56 (d, J = 7.3 Hz, 2 H, H-Ar), 7.67 (d, J = 7.3 Hz, 1 H,
(
13
H-Ar), 8.62 (d, J = 8.6 Hz, 2 H, H-Ar) ppm. C NMR (100 MHz,
13
H-Ar), 8.83 (d, J = 7.9 Hz, 2 H, H-Ar) ppm. C NMR (100 MHz,
CDCl ): δ = 21.8 (CH ), 30.1 (CH ), 100.3 (CH), 114.9 (Cq), 124.6
q, J = 272 Hz, Cq), 125.4 (q, J = 4 Hz, 2 CH), 126.3 (CH), 128.4
CDCl
3
): δ = 20.7 (CH
3 3 3
), 30.0 (CH ), 55.5 (CH ), 100.1 (CH), 113.8
3
3
3
(
(
(
2 CH), 115.7 (Cq), 125.7 (CH), 128.7 (CH), 128.8 (2 CH), 129.0
CH), 129.1 (2 CH), 129.7 (2 CH), 130.1 (CH), 131.3 (CH), 131.9
Cq), 132.2 (Cq), 137.1 (Cq), 138.0 (Cq), 142.4 (Cq), 154.3 (Cq),
(
(
(
2 CH), 128.7 (CH), 129.0 (3 CH), 129.2 (2 CH), 129.6 (CH), 130.9
CH), 131.1 (q, J = 32 Hz, Cq), 131.7 (Cq), 138.6 (Cq), 138.7 (Cq),
1
57.3 (Cq), 159.1 (Cq), 161.1 (Cq) ppm. HRMS (ESI): calcd. for
1
42.7 (Cq), 143.6 (Cq), 154.5 (Cq), 156.0 (Cq), 156.7 (Cq) ppm.
O [M + H]+ 406.1914; found 406.1913.
27 24 3
C H N
1
9
F NMR (376 MHz, CDCl
3 3
): δ = –62.39 (CF ) ppm. HRMS
+
(ESI): calcd. for C27 [M + H] 444.1682; found 444.1680.
21 3 3
H F N
2
,4-Bis(4-methoxyphenyl)-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]-
pyrimidine (9i): The reaction was carried out by following general
procedure F and starting from the 4-arylpyrrolopyrimidine 7d
7
-Methyl-6-phenyl-2-(pyridin-3-yl)-4-(m-tolyl)-7H-pyrrolo[2,3-d]-
pyrimidine (9f): The reaction was carried out by following general
procedure F and starting from 4-arylpyrrolopyrimidine 7a
(
(
50.0 mg, 0.138 mmol) and (4-methoxyphenyl)boronic acid
31.5 mg, 0.207 mmol). The crude product was purified by silica gel
(
0
50.0 mg, 0.145 mmol) and (3-pyridinyl)boronic acid (26.7 mg,
.217 mmol). The crude product was purified by silica gel column
chromatography (dichloromethane/ethyl acetate, 85:15) to afford 9f
52.3 mg, 0.139 mmol, 96% yield) as a pale yellow solid; m.p. 136–
column chromatography (petroleum ether/dichloromethane, 2:8) to
afford 9i (51.2 mg, 0.121 mmol, 88% yield) as a yellow solid; m.p.
1
1
55–156 °C (pentane). IR (ATR diamond): ν˜ = 2918, 1605, 1510,
(
–
1 1
459, 1372, 1248, 1158, 1026, 837, 750, 696 cm
): δ = 3.91 (s, 6 H, OCH ), 3.94 (s, 3 H, NCH
.85 (s, 1 H, 5-H), 7.04 (d, J = 7.9 Hz, 2 H, H-Ar), 7.09 (d, J =
.9 Hz, 2 H, H-Ar), 7.44–7.55 (m, 3 H, H-Ar), 7.56–7.63 (m, 2 H,
.
H NMR
1
1
38 °C (pentane). IR (ATR diamond): ν˜ = 3053, 2918, 1538, 1487,
373, 1290, 909, 777, 749, 700 cm . H NMR (400 MHz, CDCl
–1
1
(400 MHz, CDCl
6
7
3
3
3
),
3
):
δ = 2.50 (s, 3 H, CH
3
), 3.93 (s, 3 H, NCH ), 6.87 (s, 1 H, 5-H),
3
7
2
.32–7.36 (m, 1 H, H-Ar), 7.42–7.55 (m, 5 H, H-Ar), 7.56–7.60 (m,
H-Ar), 8.31 (d, J = 7.9 Hz, 2 H, H-Ar), 8.66 (d, J = 7.9 Hz, 2 H,
H, H-Ar), 8.04–8.14 (m, 2 H, H-Ar), 8.95 (d, J = 6.6 Hz, 1 H,
1
3
H-Ar) ppm. C NMR (100 MHz, CDCl
(CH ), 55.6 (CH ), 100.2 (CH), 113.3 (Cq), 113.8 (2 CH), 114.2 (2
CH), 128.7 (CH), 128.9 (2 CH), 129.2 (2 CH), 129.6 (2 CH), 130.5
2 CH), 131.8 (Cq), 132.0 (Cq), 132.2 (Cq), 142.4 (Cq), 154.8 (Cq),
56.0 (Cq), 157.4 (Cq), 161.1 (Cq), 161.2 (Cq) ppm. HRMS (ESI):
calcd. for C27
[M + H]+ 422.1863; found 422.1864.
3 3
): δ = 30.1 (CH ), 55.5
H-Ar) ppm. Two proton signals from the pyridine unit were miss-
ing. 1 C NMR (100 MHz, CDCl
3
3
3
3
): δ = 21.8 (CH
3 3
), 30.1 (CH ),
1
1
1
00.3 (CH), 114.8 (Cq), 126.2 (CH), 128.7 (CH), 128.9 (2 CH),
29.0 (CH), 129.2 (2 CH), 129.6 (CH), 130.0 (CH), 130.9 (CH),
31.6 (Cq), 132.1 (Cq), 132.2 (Cq), 135.1 (CH), 138.5 (Cq), 138.7
(
1
24 3 2
H N O
(
(
Cq), 143.5 (Cq), 149.7 (CH), 154.4 (Cq), 155.6 (CH), 156.7
Cq) ppm. HRMS (ESI): calcd. for C25H N [M + H] 377.1761;
21 4
+
2
-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-[4-(trifluoromethyl)phen-
yl]-7H-pyrrolo[2,3-d]pyrimidine (9j): The reaction was carried out
-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(p-tolyl)-7H-pyrrolo- by following general procedure F and starting from 4-arylpyrrolo-
found 377.1760.
2
[2,3-d]pyrimidine (9g): The reaction was carried out by following
pyrimidine 7e (50 mg, 0.125 mmol) and (4-methoxyphenyl)boronic
general procedure F and starting from 4-arylpyrrolopyrimidine 7b
acid (28.5 mg, 0.188 mmol). The crude product was purified by sil-
(50 mg, 0.145 mmol) and (4-methoxyphenyl)boronic acid (33.0 mg, ica gel column chromatography (petroleum ether/dichloromethane,
0
.217 mmol). The crude product was purified by silica gel column
7:3) to afford 9j (57.1 mg, 0.124 mmol, 99% yield) as a light green
solid; m.p. 150–152 °C (pentane). IR (ATR diamond): ν˜ = 2936,
chromatography (petroleum ether/dichloromethane, 5:5) to afford
–
1 1
9
1
1
g (56.9 mg, 0.140 mmol, 97% yield) as a yellow solid; m.p. 169– 1565, 1378, 1320, 1247, 1166, 1107, 1030, 843, 755, 695 cm . H
71 °C (pentane). IR (ATR diamond): ν˜ = 3048, 2917, 1552, 1509, NMR (400 MHz, CDCl ): δ = 3.91 (s, 3 H, OCH ), 3.95 (m, 3 H,
464, 1375, 1299, 1244, 1161, 1035, 840, 749, 700 cm . H NMR NCH ), 6.81 (s, 1 H, 5-H), 7.05 (d, J = 8.5 Hz, 2 H, H-Ar), 7.45–
3
3
–1 1
3
(
3
400 MHz, CDCl
.94 (s, 3 H, NCH
3
3
): δ = 2.48 (s, 3 H, CH
), 6.86 (s, 1 H, 5-H), 7.05 (d, J = 8.5 Hz, 2 H,
3
), 3.91 (s, 3 H, OCH
3
),
7.56 (m, 3 H, H-Ar), 7.56–7.63 (m, 2 H, H-Ar), 7.82 (d, J = 8.0 Hz,
2 H, H-Ar), 8.40 (d, J = 8.0 Hz, 2 H, H-Ar), 8.65 (d, J = 8.5 Hz,
1
3
H-Ar), 7.38 (d, J = 7.7 Hz, 2 H, H-Ar), 7.42–7.54 (m, 3 H, H-Ar), 2 H, H-Ar) ppm. C NMR (100 MHz, CDCl
3 3
): δ = 30.1 (CH ),
6
554 Eur. J. Org. Chem. 2015, 6547–6556
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A Strategy for the Triarylation of Pyrrolopyrimidines
5
2
1
5.5 (CH
3
), 99.6 (CH), 113.9 (2 CH), 114.1 (Cq), 124.6 (q, J = [8] a) H.-S. Ahn, A. Bercovici, G. Boykow, A. Bronnenkant, S.
Chackalamannil, J. Chow, R. Cleven, J. Cook, M. Czarniecki,
C. Domalski, A. Fawzi, M. Green, A. Gundes, G. Ho, M. Lau-
dicina, N. Lindo, K. Ma, M. Manna, B. McKittrick, B. Mirzai,
T. Nechuta, B. Neustadt, C. Puchalski, K. Pula, L. Silverman,
E. Smith, A. Stamford, R. P. Tedesco, H. Tsai, D. B. Tulshian,
H. Vaccaro, R. W. Watkins, X. Weng, J. T. Witkowski, Y. Xia,
H. Zhang, J. Med. Chem. 1997, 40, 2196–2210; b) R. He, S. M.
Ching, Y. Lam, J. Comb. Chem. 2006, 8, 923–928; c) L. G. J.
Hammarstrom, D. B. Smith, F. X. Talamas, Tetrahedron Lett.
71 Hz, Cq), 125.7 (q, J = 4 Hz, 2 CH), 129.0 (2 CH), 129.1 (CH),
29.2 (2 CH), 129.3 (2 CH), 129.7 (2 CH), 131.5 (q, J = 32 Hz,
Cq), 131.7 (Cq), 131.8 (Cq), 142.5 (Cq), 143.5 (Cq), 154.6 (Cq),
55.0 (Cq), 157.6 (Cq), 161.3 (Cq) ppm. 19F NMR (376 MHz,
CDCl ): δ = –62.61 (CF ) ppm. HRMS (ESI): calcd. for
O [M + H] 460.1631; found 460.1629.
1
3
3
+
27 21 3 3
C H F N
2
-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(pyridin-3-yl)-7H-
pyrrolo[2,3-d]pyrimidine (9k): The reaction was carried out by fol-
lowing general procedure F and starting from the 4-arylpyrrolopyr-
imidine 7f (50 mg, 0.155 mmol) and (4-methoxyphenyl)boronic
acid (28.5 mg, 0.233 mmol). The crude product was purified by sil-
ica gel column chromatography (dichloromethane/ethyl acetate,
2007, 48, 2823; d) R. V. Kalla, E. Elzein, T. Perry, X. Li, A.
Gimbel, M. Yang, D. Zeng, J. Zablocki, Bioorg. Med. Chem.
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[
9] a) I. Cerna, R. Pohl, B. Klepetarova, M. Hocek, Org. Lett.
2006, 8, 5389–5392; b) I. Cˇ er nˇ a, R. Pohl, B. Klepetá rˇ ová, M.
6:4) to afford 9k 52.6 mg, 0.134 mmol, 86% yield) as a yellow solid;
Hocek, J. Org. Chem. 2008, 73, 9048; c) W. K.-D. Brill, C. Riva-
Toniolo, S. Müller, Synlett 2001, 1097–1100; d) L. Vandromme,
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–
1
1
583, 1557, 1488, 1374, 1302, 1239, 1163, 1024, 853, 752, 703 cm .
1
H NMR (400 MHz, CDCl
H, NCH ), 6.83 (s, 1 H, 5-H), 7.03 (d, J = 8.3 Hz, 2 H, H-Ar),
.44–7.55 (m, 4 H, H-Ar), 7.58 (d, J = 7.4 Hz, 2 H, H-Ar), 8.62
3 3
): δ = 3.89 (s, 3 H, OCH ), 3.93 (s, 3
3
2002, 124, 1594–1596; f) L. Vandromme, S. Piguel, O. Lozach,
7
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183–186.
1
3
(
m, 3 H, H-Ar), 8.84 (s, 1 H, H-Ar), 9.58 (s, 1 H, H-Ar) ppm.
NMR (100 MHz, CDCl ): δ = 30.1 (CH ), 55.5 (CH ), 99.4 (CH),
13.9 (2 CH), 114.0 (Cq), 124.1 (CH), 128.8 (Cq), 128.9 (2 CH),
29.0 (CH), 129.1 (2 CH), 129.6 (2 CH), 131.6 (Cq), 131.7 (Cq),
C
3
3
3
1
1
1
36.1 (CH), 143.4 (Cq), 150.0 (CH), 150.5 (CH), 153.4 (Cq), 154.8 [10] M. Kroemer, M. Klecka, L. Slavetinska, B. Klepetarova, M.
(
Cq), 157.6 (Cq), 161.2 (Cq) ppm. HRMS (ESI): calcd. for
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O [M + H]+ 393.1710; found 393.1709.
25 21 4
H N
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The financial support by the Institut de Chimie Organique et Ana-
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Eur. J. Org. Chem. 2015, 6547–6556
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6555

V. Prieur, M. D. Pujol, G. Guillaumet
FULL PAPER
Adv. Synth. Catal. 2013, 355, 1640–1648; k) H. N. Nguyen,
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Received: May 14, 2015
Published Online: August 24, 2015
6556
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6547–6556