Microwave-Assisted Synthesis of Substituted Pyrrolo[2,3-d]pyrimidines

Article abstract of DOI:10.1002/ejoc.201301496

A new synthetic route to triaryl pyrrolo[2,3-d]pyrimidines from common 4,6-dichloropyrimidine has been developed. The triarylated compounds are synthesized by three cross-coupling reactions using three different catalysts. The introduction of a C-6 aryl group was achieved in a two-step process under Sonogashira conditions [Pd(dba)₂/CuI] followed by intramolecular cyclization, and application of Suzuki-Miyaura conditions [Pd(PPh₃)₄; PdCl₂(PPh₃)₂] led to C-4 and C-5 diarylation. This sequence allows a flexible synthetic approach to highly arylated pyrrolopyrimidines containing different aryl groups.

Full text of DOI:10.1002/ejoc.201301496

FULL PAPER
DOI: 10.1002/ejoc.201301496
Microwave-Assisted Synthesis of Substituted Pyrrolo[2,3-d]pyrimidines
Vanessa Prieur,[a,b] Jaime Rubio-Martínez,[c] Mercè Font-Bardia,[d] Gérald Guillaumet,*[a]
and M. Dolors Pujol*[b]
Keywords: Synthetic mwthods / C–C coupling / Cross-coupling / Nitrogen heterocycles / Microwave chemistry / Drug
discovery
A new synthetic route to triaryl pyrrolo[2,3-d]pyrimidines
from common 4,6-dichloropyrimidine has been developed.
The triarylated compounds are synthesized by three cross-
coupling reactions using three different catalysts. The intro-
duction of a C-6 aryl group was achieved in a two-step pro-
cess under Sonogashira conditions [Pd(dba)2/CuI] followed
by intramolecular cyclization, and application of Suzuki–
Miyaura conditions [Pd(PPh3)4; PdCl2(PPh3)2] led to C-4 and
C-5 diarylation. This sequence allows a flexible synthetic ap-
proach to highly arylated pyrrolopyrimidines containing dif-
ferent aryl groups.
opment and functionalization of biologically active com-
pounds containing the pyrrolo[2,3-d]pyrimidine substruc-
ture.[9]
Introduction
Pyrrolo[2,3-d]pyrimidines (IUPAC numbering is used
throughout the manuscript), also known as 7-deazapurines,
are an important class of heterocyclic compound contain-
ing a pyrrole ring with pyrimidine fused at the α,β-position.
The pyrrolo[2,3-d]pyrimidine core is found in a wide range
of natural compounds, including nucleoside antibiotics such
as toyocamycin, sangivamycin and tubercidin.[1] Its wide
and versatile spectrum of biological activities has led to its
incorporation in synthetic biologically active compounds
such as neurogenesis inductors by GSK-3b inhibition
(TWS119, Figure 1),[2] antitumor (ACK1 inhibitors with
IC50 = 0.62 μm, Figure 1),[3] anti-inflammatory agents,[4]
and analgesic derivatives.[5] In addition to these bioapplica-
tions, other structurally diverse substituted purines[6] and 7-
deazapurines[7,8] have been studied for their photophysical
properties as, for example, electronic material and blue-light
emitters. In recent years, great efforts have been dedicated
to the synthesis of this heterocyclic system and to the devel-
Figure 1. Purines and 7-deazapurines.
[a] Institut de Chimie Organique et Analytique (ICOA), Université
d’Orléans, UMR CNRS 7311,
General methods for the preparation of pyrrolopyrimid-
ines remain limited.[10] The majority of procedures provide
C-4 monosubstituted or C-2, N-7 disubstituted compounds
and there have been few general approaches to the function-
alization of this heterocycle system.[11] In general, com-
pounds possessing this nitrogenated scaffold can be pre-
pared from alicyclic reagents in basic media.[12] A synthesis
of pyrrolo[2,3-d]pyrimidines by the cyclization of appropri-
ately substituted pyrrole was reported by Rashad et al.[13]
and Hilmy et al.[14] The standard method entails the intro-
duction of the pyrrole ring to bridge the pyrimidine at the
C-4, C-5 positions. Other previously published synthetic ap-
proaches to pyrrolopyrimidines have used halogenated pyr-
imidines as the common intermediate, which are converted
Rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
E-mail: gerald.guillaumet@univ-orleans.fr
http://www.univ-orleans.fr/icoa/synthese
[b] Laboratori de Química Farmacèutica (Unitat Associada al
CSIC), Facultat de Farmàcia, Universitat de Barcelona,
Av. Diagonal 643, 08028 Barcelona, Spain
E-mail: mdpujol@ub.edu
http://www.ub.edu/farmacia/recerca/linies/
[c] Laboratori de Química Física. Facultat de Química, Universitat
de Barcelona,
08028 Barcelona, Spain
[d] Unitat de Difracció de RX. Centres Científics i Tecnològics de
la Universitat de Barcelona (CCiTUB), Universitat de
Barcelona,
Solé i Sabarís 1–3, 08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301496.
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Microwave-Assisted Synthesis of Pyrrolo[2,3-d]pyrimidines
into the corresponding aminopyrimidines.[15] The cross- irradiation under mild to moderate conditions from stable
coupling reaction of aminopyrimidines with vinyl stannanes starting material.
followed by cyclization furnishes the pyrrolopyrimidines
The starting 5-alkynylpyrimidines 4 can be prepared eas-
without functionalization of the five-membered ring.[15] The ily by a Sonogashira type alkynylation[21] of 6-chloro-5-
reaction of 4-amino-5-bromopyrimidine through ketone α- iodo-4-(methylamino)pyrimidine by using commercial alk-
arylation with acetophenone provides the 6-phenylpyrrolo- ynylbenzenes under microwave assistance. The use of micro-
pyrimidine in 62% yield.[16] Recently, Kopecky and co- wave irradiation under palladium catalysis has been investi-
workers[3] reported a general route with which to access the gated and applied to organic synthesis in both academia
bicyclic structure from 4,6-diamino-5-iodopyrimidine in- and industry.[22] The Sonogashira reaction is chemoselective
volving an intramolecular palladium-catalyzed Heck reac- and the yield is not affected by the electronic properties of
tion. The cyclization reaction of 2-alkynylanilines consti- the 4-substituted aryl alkyne (Scheme 2). The 6-chloro-5-
tutes an interesting procedure with which to obtain 2-sub- iodo-4-(methylamino)pyrimidine (3) used in this reaction
stituted indoles, azaindoles or other heterocyclic cores in- was prepared by nucleophilic substitution of the 4,6-di-
cluding pyrrolopyrimidines.[17] However, this intramolecu- chloropyrimidine with methylamine at C-4 followed by
lar cyclization requires a base and high temperatures (180– iodination under classical conditions.[17]
200 °C).[17,18]
Despite the wide range of methods available for the prep-
aration of pyrrolopyrimidines, very few of them provide an
efficient procedure with which to obtain the heterocyclic
system with a range of substituents. To the best of our
knowledge, the limited number of approaches available for
the synthesis and functionalization of pyrrolo[2,3-d]pyr-
imidines do not include the preparation of 4,5,6-triarylpyr-
rolopyrimidines. Only 2,4,7-triarylpyrrolo[2,3-d]pyrimid-
ines[19] and 2,6,8-triarylpurines,[20] possessing optical or
adenosine antagonist properties, respectively, have been re-
ported.
Scheme 2. Alkynylation of iodopyrimidines 3.
The intramolecular cyclization in the presence of base
(Cs2CO3) and a catalytic amount of CuI (1 mol-%) under
microwave irradiation afforded bicyclic heterocycle 5 in ex-
Results and Discussion
cellent yield with good tolerance of different substituent
With the aim of developing an efficient route that is suit- groups. These conditions allowed us to work at lower tem-
able for the triarylation of pyrrolopyrimidines, we designed peratures (100 °C) than those published by other authors
the following general synthesis from the commercially avail- (180–200 °C).[17,18] Applying the same conditions but per-
able precursor 4,6-dichloropyrimidine (1; Scheme 1). This forming the cyclization without CuI provided higher yields,
synthesis was performed in seven steps by using microwave showing that the reaction works even better without the
Scheme 1. Two synthetic routes to the triarylated pyrrolopyrimidines 8.
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G. Guillaumet, M. D. Pujol et al.
FULL PAPER
copper catalyst (Scheme 3). The optimized protocol in- Table 1. Suzuki–Miyaura cross-coupling reactions at the 4-position
of heterocycle 5 leading to 4,6-disubstituted pyrrolopyrimidines 6.
volved treating diarylalkyne with cesium carbonate in
acetonitrile and heating at 100 °C for 30–90 min in a micro-
wave system. Ring closure was achieved to give the desired
product 5 in only one step from the common intermediate
4; the product was used in the next step without further
purification.
Scheme 3. Intramolecular cyclization of diarylalkynyl derivatives 4.
In a preliminary study, the direct halogenation of 4-
chloropyrrolopyrimidines 5 by using N-bromosuccinimide
(NBS) or N-iodosuccinimide (NIS), under microwave as-
sistance, provided the corresponding 5-bromopyrrolopyri-
midines (87%) or 5-iodopyrrolopyrimidines (90%)
(Scheme 4). Replacement of the bromo or iodo group at-
tached at the C-5 position of the pyrrolopyrimidines by
using the corresponding arylboronic acid provided the aryl-
ated compounds 9 in yields of 33 or 70%, from the bromo
or iodo derivative, respectively.
In the following step, the isolated 4-chlorodiarylated pyr-
rolopyrimidines 9 were arylated by using aryl boronic acids
and Suzuki–Miyaura catalysts in 83% yield. This synthetic
procedure furnished triarylpyrrolopyrimidines 8 in seven
steps with an overall yield of 12–32%.
With these results in hand, we attempted to generate tri-
arylpyrrolopyrimidines from intermediate 5 by using an al-
ternative route, reversing the order of arylation of the pyr-
rolopyrimidines so that arylation would first take place at
C-4 and then at C-5. Thus, 4-arylderivatives 6 were ob-
tained by treatment of 4-chloropyrrolopyrimidines 5 with
arylboronic acids under Suzuki–Miyaura cross-coupling
conditions[23] by using a microwave heat source.[24] The re-
action yields were good to excellent (91–100%; Table 1),
and the reaction incorporating the phenyl derivatives was
found to be chemoselective. This method thus provides ef-
ficient access to diarylated compounds.
[a] Yield of isolated compound.
Direct arylation of C-5 was not achieved under a wide
range of tested conditions. As a result, the diarylpyrrolopyr- for a purification step (Table 2). Halogenation at C-5 was
imidines were iodinated at the C-5 position by electrophilic performed regioselectively. Interestingly, analysis of the
1
substitution with N-iodosuccinimide[25] under microwave iodo compounds by H NMR spectroscopy carried out at
radiation at 100 °C with nearly quantitative conversion, 30, 100, and 180 days after their preparation showed higher
very high yields, and sufficient purity as to obviate the need stability at room temperature when the compounds were
Scheme 4. Diarylation of pyrrolopyrimidines.
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Microwave-Assisted Synthesis of Pyrrolo[2,3-d]pyrimidines
stored without a solvent. Following this study, the iodo Table 3. Suzuki–Miyaura cross-coupling reaction at C-5 of pyrrolo-
pyrimidines 7..
compounds in chloroform solution showed complete sta-
bility after 30 days at room temperature. It should be em-
phasized that carrying out the C-4 arylation of the pyrrolo-
pyrimidines before C-5 iodination avoided the Cl/I ex-
change that impedes the chemoselective arylation.
Table 2. Iodination of pyrrolopyrimidines 6.
[a] Yield of isolated compound.
The third aryl group at the C-5 position of 4,6-diaryl-5-
iodopyrrolo[2,3-d]pyrimidines 7 was introduced by treat-
ment with arylboronic acids under Suzuki–Miyaura cross-
[a] Yield of isolated compound.
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G. Guillaumet, M. D. Pujol et al.
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coupling conditions. After workup, a new iodination pro-
cess with NIS was carried out, which allowed some ad-
ditional starting material to be recovered, separated, and
reused. Microwave assistance enabled a rapid synthesis of a
variety of triaryl pyrrolopyrimidines with different substitu-
ents. It was clear that meta and para substituents on the
arylboronic acid (Ar2) were well-tolerated, whereas ortho
substituents hampered the reaction as a result of steric hin-
drance (Table 3, entry 5). The ortho, meta or para substitu-
ents of the aryl groups attached at C-4 of the pyr-
rolopyrimidine core did not modify the arylation process
(Table 3, entries 1, 6 and 9). Whereas the presence of a sub-
stituent of the aryl group linked to C-6 (Table 3, cf. entry 1
with entries 10 and 11) had a significant impact on the rate
of the Suzuki–Miyaura reaction, the electron-donating or
withdrawing nature of the substituents was not influential.
Increasing the number of equivalents of the reactant, as
well as the reaction time and temperature did not favor the
reaction. The optimized procedure afforded the desired tria-
ryl-substituted pyrrolopyrimidines in 35–50% overall yield
in seven steps, which constitutes a significant improvement
on the previously described route.
The molecular structure of the triaryl-substituted pyr-
rolo[2,3-d]pyrimidine 8k (Table 3, entry 11) was determined
by means of X-ray diffraction studies, and the crystallo-
graphic data and structural refinement parameters have
been deposited with the CCDC. Colorless crystals of 8k
were obtained by slow diffusion of hexane over a saturated
ethyl acetate solution. The compound crystallized in the
prism space group C2/c. The crystallographic structure and
atom numbering are given in Figure 2, which shows a per-
spective view of compound 8k. The crystallographic struc-
ture reveals the orientation of the three aryl substituents
with respect to the pyrrolopyrimidine system.
Conclusions
The chemistry outlined here provides an efficient path-
way for the synthesis of triarylated pyrrolo[2,3-d]pyrimid-
ines through three cross-coupling reactions catalyzed by
palladium under microwave irradiation. The high yields ob-
tained in the different steps suggest that this process has
considerable promise for the synthesis of pyrrolopyrimid-
ines bearing three different (or equivalent) arylated substit-
uents (overall yield 35–50%). This method allows arylation
at C-4, C-5 and C-6 of pyrrolopyrimidines and should be
of interest for the synthesis of medicinal and photoactive
structures.
Experimental Section
General: Microwave-assisted reactions were carried out with a Bi-
otage Initiator Microwave synthesis instrument and the internal
temperature was measured by an IR sensor. The reactions were
monitored by thin-layer chromatography (TLC) analysis using sil-
ica gel (60 F254) plates. Compounds were visualized by UV irradia-
tion. Column chromatography was performed with silica gel 60
(230–400 mesh, 0.040–0.063 mm). Melting points (mp) were ob-
tained with a melting point apparatus with a digital thermometer
in open capillary tubes and are reported without correction. IR
spectra were obtained with an FTIR Infrared Spectrophotometer.
1H and 13C NMR spectra were recorded at 250 MHz (13C,
63 MHz), 300 (13C, 75.5 MHz), or 400 MHz (13C, 100 MHz).
Chemical shifts (δ) (multiplicity, coupling constants and integra-
tion) are reported in parts per million (ppm) relative to the central
peak of the solvent: CDCl3 [δ = 7.26 (H) and 77.16 (C) ppm],
CD3OD [δ = 3.31 (H) and 49.45 (C) ppm], [D6]DMSO [δ = 2.49
(H) and 39.51 (C) ppm] as internal standards. The following ab-
breviations are used for the proton spectra multiplicities: s singlet,
d doublet, t triplet, q quadruplet, m multiplet, dd doublet of dou-
blets, dt doublet of triplets and br. broad signal. Coupling con-
stants (J) are reported in Hertz (Hz). High-resolution mass spectra
(HRMS) were recorded with a time-of-flight mass spectrometer fit-
ted with either an electrospray (ESI) or atmospheric pressure ion-
ization (APCI). All reagents were of high quality or were purified
before use. Organic solvents were of analytical grade or were puri-
fied by standard procedures.
6-Chloro-N-methylpyrimidin-4-amine (2): To a solution of 4,6-
dichloropyrimidine (1; 200 mg, 1.34 mmol) in 2-propanol (1.3 mL),
triethylamine (0.22 mL, 1.61 mmol) and MeNH2·HCl (108.8 mg,
1.61 mmol) were added. The reaction was stirred and heated to the
reflux temperature of 2-propanol until complete consumption of
the starting material as determined by TLC analysis (4 h). After
cooling, the solvent was removed under vacuo. Water (15 mL) was
added and the mixture was extracted with ethyl acetate (3ϫ
15 mL). The combined organic layers were washed with NH4Cl
(10 mL). Evaporation of the solvent under reduced pressure gave
the crude product, which was purified by silica gel column
chromatography (CH2Cl2/ethyl acetate, 6:4) to afford 2 (150.7 mg,
1.05 mmol, 78%) as a white solid, m.p. 136–138 °C (EtOAc) [136–
138 °C (hexane)].[26] Rf = 0.22 (CH2Cl2/ethyl acetate, 6:4). IR (ATR
diamond): ν = 3246, 3083, 2967, 1619, 1568, 1429, 1384, 1329,
˜
1227, 1143, 1092, 976, 887, 834, 741, 708 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.92 (d, J = 4.3 Hz, 3 H), 5.87 (s, 1 H),
6.33 (s, 1 H), 8.31 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 28.3, 99.9, 158.2, 159.8, 164.0 ppm. HRMS (ESI): calcd. for
C5H7ClN3 [M + H]+ 144.0323; found 144.0322.
Figure 2. Molecular structure of 8k. Displacement ellipsoids are
drawn at the 30% probability level and H atoms are represented
by circles of arbitrary radii.
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Microwave-Assisted Synthesis of Pyrrolo[2,3-d]pyrimidines
6-Chloro-5-iodo-N-methylpyrimidin-4-amine (3): A solution of pyr-
imidine 2 (2 g, 13.9 mmol) in acetonitrile (30 mL) was transferred
to a microwave reaction tube and irradiated in a microwave oven
twice at 100 °C for 15 min with previous addition of NIS (9.4 g,
41.7 mmol). The progress of the reaction was monitored by TLC
6-Chloro-N-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethynyl}-
pyrimidin-4-amine (4c): The reaction was carried out by following
general procedure A starting from the iodinated pyrimidine 3
(150 mg, 0.56 mmol) and 1-ethynyl-4-(trifluoromethylbenzene)
(0.2 mL, 1.11 mmol). The crude product was purified by silica gel
(CH2Cl2/ethyl acetate, 6:4). After cooling, the solvent was removed, column chromatography (petroleum ether/CH2Cl2/acetone, 8:1:1)
then CH2Cl2 (50 mL) was added and the organic layer was washed
with aqueous saturated Na2S2O3 (2ϫ 50 mL), and NaOH (10%,
2ϫ 50 mL). Evaporation of the solvent under reduced pressure
gave the crude product, which was purified by recrystallization
from ethanol (20 mL) to afford 3 (3.27 g, 12.1 mmol, 87%) as pale-
yellow crystals; m.p. 146–148 °C (EtOH). Rf = 0.50 (CH2Cl2/ethyl
followed by recrystallization (CH2Cl2/pentane) to afford 4c
(172.7 mg, 0.55 mmol, 99 %) as a pale-yellow solid; m.p. 107–
109 °C (pentane). Rf = 0.17 (petroleum ether/CH2Cl2/acetone,
8:1:1). IR (ATR diamond): ν = 3360, 2925, 1562.1509, 1396, 1322,
˜
1276, 1228, 1167, 1090, 1064, 903, 836, 781, 736 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.13 (d, J = 5.0 Hz, 3 H), 5.73 (s, 1 H),
7.64 (s, 4 H), 8.37 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 28.6, 81.9, 100.3, 100.6, 123.9 (J = 272 Hz), 125.6 (J = 4 Hz),
125.8 (J = 1 Hz), 131.1 (J = 33 Hz), 132.0, 156.7, 159.8, 163.0 ppm.
acetate, 6:4). IR (ATR diamond): ν = 3292, 2936, 1557, 1499, 1389,
˜
1
1326, 1263, 1237, 1179, 1122, 1080, 1001, 888, 762 cm–1. H NMR
(250 MHz, CDCl3): δ = 3.06 (d, J = 4.9 Hz, 3 H), 5.64 (s, 1 H),
8.24 (s, 1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 29.45, 79.6, 19F NMR (376 MHz, CDCl3): δ = –62.94 (CF3) ppm. HRMS
157.3, 162.2, 163.0 ppm. HRMS (ESI): calcd. for C5H6ClIN3 [M +
(ESI): calcd. for C14H10ClF3N3 [M + H]+ 312.0510; found
312.0511.
H]+ 269.9289; found 269.9291.
General Procedure B (Cyclization): A solution of alkyne 4a–c
(1.0 mmol) and cesium carbonate (1.0 mmol) in acetonitrile
(4.5 mL) was transferred to a microwave reaction tube and irradi-
ated in a microwave oven at 100 °C for the required time. The pro-
gress of the reaction was monitored by TLC. After cooling, the
solvent was removed under vacuo. Water (20 mL) was added to the
mixture and the crude material was extracted with ethyl acetate
(3ϫ 15 mL). The combined organic phases were washed with aque-
ous saturated Na2CO3 (15 mL) and brine (15 mL). Purification was
performed by column chromatography on silica gel to give the cor-
responding pure product 5.
General Procedure A (Sonogashira Coupling): A mixture containing
3 (1.0 mmol), alkyne (2.0 mmol), Pd(dba)2 (0.03 mmol), tri(2-furyl)
phosphine (0.06 mmol), and CuI (0.04 mmol) in anhydrous THF
(1 mL) and anhydrous triethylamine (3.5 mL) was transferred to a
microwave reaction tube and irradiated in a microwave oven at
100 °C for 30 min. The progress of the reaction was monitored by
TLC. After cooling, the mixture was diluted with aqueous satu-
rated NH4Cl (15 mL) and the aqueous phase was extracted with
ethyl acetate (3ϫ 20 mL). The combined organic phases were dried
with MgSO4 and filtered through Celite. Evaporation of the solvent
under reduced pressure gave the crude product, which was purified
by silica gel column chromatography.
4-Chloro-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine (5a): The
reaction was carried out by following general procedure B starting
from the alkyne 4a (800 mg, 3.28 mmol) and microwave irradiation
was applied for 30 min. The crude product was purified by silica
gel column chromatography (petroleum ether/CH2Cl2/acetone,
8:1:1) followed by recrystallization (CH2Cl2/pentane) to afford 5a
(795.2 mg, 3.26 mmol, 99 %) as a pale-yellow solid; m.p. 151–
153 °C (pentane). Rf = 0.18 (petroleum ether/CH2Cl2/acetone,
6-Chloro-N-methyl-5-(2-phenylethynyl)pyrimidin-4-amine (4a); Ge-
neral Procedure A: The reaction was carried out by following gene-
ral procedure A starting from the iodinated pyrimidine 3 (1 g,
3.71 mmol) and phenylacetylene (0.82 mL, 7.42 mmol). The crude
product was purified by silica gel column chromatography (petro-
leum ether/CH2Cl2/acetone, 8:1:1) followed by recrystallization
(CH2Cl2/pentane) to afford 4a (842.2 mg, 3.46 mmol, 93%) as a
white solid; m.p. 113–115 °C (pentane). Rf = 0.28 (petroleum ether/
8:1:1). IR (ATR diamond): ν = 3741, 2946, 1585, 1541, 1485, 1432,
˜
1405, 1347, 1237, 1184, 1127, 1013, 938, 855, 755, 702 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H), 6.62 (s, 1 H), 7.44–
7.58 (m, 5 H), 8.64 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 30.5, 98.8, 117.7, 129.0, 129.3, 129.4, 130.9, 143.4, 150.6, 151.4,
152.7 ppm. HRMS (ESI): calcd. for C13H11ClN3 [M + H]+
244.0636; found 244.0637.
CH Cl /acetone, 8:1:1). IR (ATR diamond): ν = 3397, 1564,
˜
2
2
1490.1392, 1274, 1230, 1138, 1088, 906, 848, 749, 684 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 3.12 (d, J = 5.0 Hz, 3 H), 5.76 (s, 1
H), 7.34–7.44 (m, 3 H), 7.51–7.60 (m, 2 H), 8.35 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 28.6, 79.6, 101.0, 102.3, 122.0, 128.7,
129.5, 131.8, 156.2, 159.2, 163.0 ppm. HRMS (ESI): calcd. for
C13H11ClN3 [M + H]+ 244.0636; found 244.0637.
4-Chloro-6-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimid-
ine (5b): The reaction was carried out by following general pro-
cedure B starting from the alkyne 4b (267.6 mg, 0.98 mmol) and
microwave irradiation was applied for 90 min. The crude product
was purified by silica gel column chromatography (petroleum ether/
CH2Cl2/acetone, 8:1:1) followed by recrystallization (CH2Cl2/pent-
ane) to afford 5b (254.2 mg, 0.93 mmol, 95%) as a pale-yellow so-
lid; m.p. 134–136 °C (pentane). Rf = 0.24 (petroleum ether/CH2Cl2/
6-Chloro-5-[2-(4-methoxyphenyl)ethynyl]-N-methylpyrimidin-4-
amine (4b): The reaction was carried out by following general pro-
cedure A starting from the iodinated pyrimidine 3 (150 mg,
0.56 mmol) and 1-ethynyl-4-methoxybenzene (147.1 mg,
1.11 mmol). The crude product was purified by silica gel column
chromatography (petroleum ether/CH2Cl2/acetone, 70:15:15) fol-
lowed by recrystallization (CH2Cl2/pentane) to afford 4b (143.8 mg,
0.53 mmol, 94%) as a white solid; m.p. 131–133 °C (pentane). Rf
= 0.30 (petroleum ether/CH2Cl2/acetone, 70:15:15). IR (ATR dia-
acetone, 8:1:1). IR (ATR diamond): ν = 3838, 3744, 2950, 1613,
˜
1590, 1544, 1492, 1348, 1291, 1244, 1174, 1133, 1034, 940, 839,
1
805, 772, 741, 706 cm–1. H NMR (400 MHz, CDCl3): δ = 3.83 (s,
mond): ν = 3312, 2927, 2202, 1564, 1504, 1460, 1388, 1352, 1278,
˜
3 H), 3.88 (s, 3 H), 6.56 (s, 1 H), 7.00–7.07 (m, 2 H), 7.43–7.50 (m,
2 H), 8.63 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.5,
55.6, 98.1, 114.5, 117.8, 123.2, 130.7, 143.4, 150.3, 151.1, 152.7,
160.6 ppm. HRMS (ESI): calcd. for C14H13ClN3O [M + H]+
274.0742; found 274.0744.
1251, 1170, 1137.1086, 1031, 902, 831, 779, 731 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.11 (d, J = 5.0 Hz, 3 H), 3.84 (s, 3 H),
5.75 (s, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 2 H),
8.33 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.5, 55.5,
78.3, 101.3, 102.5, 114.0, 114.3, 133.3, 156.0, 158.9, 160.6,
162.9 ppm. HRMS (ESI): calcd. for C14H13ClN3O [M + H]+
274.0742; found 274.0743.
4-Chloro-7-methyl-6-[4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]-
pyrimidine (5c): The reaction was carried out by following general
Eur. J. Org. Chem. 2014, 1514–1524
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1519

G. Guillaumet, M. D. Pujol et al.
FULL PAPER
procedure B starting from the alkyne 4c (296.6 mg, 0.95 mmol) and
microwave irradiation was applied for 30 min. The crude product
was purified by silica gel column chromatography (petroleum ether/
CH2Cl2/acetone, 8:1:1) followed by recrystallization (CH2Cl2/pent-
afford 6c (178.4 mg, 0.60 mmol, 96%) as a white solid. Rf = 0.48
(CH2Cl2/ethyl acetate, 8:2); m.p. 94–96 °C (ethyl acetate). IR (ATR
diamond): ν = 3052, 2921, 2855, 1732, 1609, 1554, 1443, 1331,
˜
1261, 1180, 1017, 938, 834, 785, 759, 698 cm–1 1H NMR
.
ane) to afford 5c (98%, 290.6 mg, 0.93 mmol) as a yellow solid; (300 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.85 (s, 3 H), 6.84 (s, 1 H),
m.p. 167–169 °C (pentane). Rf = 0.27 (petroleum ether/CH2Cl2/
7.32 (d, J = 8.0 Hz, 2 H), 7.48–7.51 (m, 5 H), 8.06 (d, J = 8.0 Hz,
2 H), 8.96 (s, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 21.6,
30.2, 100.1, 115.8, 128.9, 128.9, 129.0, 129.3, 129.6, 131.5, 135.6,
140.3, 142.8, 151.4, 153.5, 156.8 ppm. HRMS (ESI): calcd. for
acetone, 8:1:1). IR (ATR diamond): ν = 3743, 2927, 1583, 1544,
˜
1502, 1475, 1447, 1411, 1319, 1262, 1235, 1168, 1119, 1065, 1013,
1
944, 859, 804, 774, 745, 713 cm–1. H NMR (400 MHz, CDCl3): δ
= 3.87 (s, 3 H), 6.70 (s, 1 H), 7.68 (d, J = 8.2 Hz, 2 H), 7.79 (d, J C20H18N3 [M + H]+ 300.1495; found 300.1500.
= 8.2 Hz, 2 H), 8.68 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
4-(4-Methoxyphenyl)-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimid-
δ = 30.6, 99.9, 117.6, 124.0 (J = 272 Hz), 126.1 (J = 4 Hz), 129.6,
131.4 (J = 33 Hz), 134.5 (J = 1 Hz), 141.5, 152.0, 152.9 ppm. 19F
NMR (376 MHz, CDCl3): δ = –62.80 (CF3) ppm. HRMS (ESI):
calcd. for C14H10ClF3N3 [M + H]+ 312.0510; found 312.0513.
ine (6d): The reaction was carried out by following general pro-
cedure C starting from 4-chloropyrimidine 5a (150 mg, 0.62 mmol)
and 4-methoxyphenylboronic acid (98.2 mg, 0.65 mmol). The crude
product was purified by silica gel column chromatography
(CH2Cl2/ethyl acetate, 6:4) to afford 6d (194.5 mg, 0.62 mmol,
100%) as a yellow solid. Rf = 0.48 (CH2Cl2/ethyl acetate, 8:2); m.p.
General Procedure C (Suzuki–Miyaura Coupling at C-4): Under ar-
gon, a mixture of compound 5a–c (1.0 mmol), boronic acid
(1.05 mmol), sodium carbonate (2.0 mmol), and tetrakis(triphenyl-
phosphine)palladium (0.02 mmol) in a degassed solvent mixture of
174–176 °C (ethyl acetate). IR (ATR diamond): ν = 3054, 2921,
˜
2845, 1550, 1512, 1439, 1328, 1247, 1172, 1021, 937, 851, 756 cm–1.
DME (3.8 mL) and H2O (0.6 mL) was transferred to a microwave 1H NMR (300 MHz, CDCl3): δ = 3.89 (s, 3 H), 3.90 (s, 3 H), 6.87
reaction tube and irradiated in a microwave oven at 100 °C for
60 min. The progress of the reaction was monitored by TLC. 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). Evaporation of the solvent under reduced
pressure gave the crude product, which was purified by silica gel
column chromatography.
(s, 1 H), 7.07 (d, J = 8.2 Hz, 2 H), 7.47–7.59 (m, 5 H), 8.17 (d, J
= 8.2 Hz, 2 H), 8.96 (s, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 30.1, 55.8, 100.0, 114.3, 115.4, 128.9, 129.0, 129.3, 130.4, 131.0,
131.6, 142.6, 151.4, 153.4, 160.6, 161.3 ppm. HRMS (ESI): calcd.
for C20H18N3O [M + H]+ 316.1444; found 316.1447.
7-Methyl-6-phenyl-4-[4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]-
pyrimidine (6e): The reaction was carried out by following general
procedure C starting from 4-chloropyrimidine 5a (150 mg,
0.62 mmol) and 4-(trifluoromethyl)phenylboronic acid (122.8 mg,
0.65 mmol). The crude product was purified by silica gel column
chromatography (CH2Cl2/ethyl acetate, 8:2) to afford 6e (213.7 mg,
0.60 mmol, 98%) as a beige solid. Rf = 0.57 (CH2Cl2/ethyl acetate,
7-Methyl-6-phenyl-4-(3-tolyl)-7H-pyrrolo[2,3-d]pyrimidine (6a): The
reaction was carried out by following general procedure C starting
from 4-chloropyrimidine 5a (450 mg, 1.85 mmol) and 3-tolylbo-
ronic acid (263.6 mg, 1.94 mmol). The crude product was purified
by silica gel column chromatography (CH2Cl2/ethyl acetate, 7:3) to
afford 6a (507.4 mg, 1.69 mmol, 91%) as a pale-yellow solid. Rf =
8:2); m.p. 137–139 °C (ethyl acetate). IR (ATR diamond): ν = 2960,
˜
0.32 (CH2Cl2/ethyl acetate, 6:4); m.p. 109–111 °C (ethyl acetate). 2920, 2849, 1736, 1620, 1555, 1493, 1466, 1400, 1327, 1307, 1265,
IR (ATR diamond): ν = 3836, 3741, 2922, 1698, 1560, 1490, 1468,
1219, 1185, 1165, 1103, 1064, 1014, 936, 850, 808, 783, 753, 730,
˜
1
1396, 1343, 1268, 1217, 1078, 1014, 892, 814, 772, 745 cm–1. 1H
699 cm–1. H NMR (300 MHz, CDCl3): δ = 3.92 (s, 3 H), 6.85 (s,
NMR (400 MHz, CDCl3): δ = 2.47 (s, 3 H), 3.89 (s, 3 H), 6.86 (s, 1 H), 7.49–7.57 (m, 5 H), 7.81 (d, J = 8.0 Hz, 2 H), 8.28 (d, J =
1 H), 7.30–7.32 (m, 1 H), 7.40–7.58 (m, 6 H), 7.91–8.01 (m, 2 H),
8.0 Hz, 2 H), 9.02 (s, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
8.99 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5, 29.9, = 30.3, 99.4, 116.2, 124.2 (J = 271 Hz), 125.8 (J = 4 Hz), 129.0,
99.8, 115.8, 125.9, 128.5, 128.7, 128.8, 129.1, 129.2, 130.6, 138.2,
138.4, 142.7, 151.3, 153.3, 156.8 ppm. HRMS (ESI): calcd. for
C20H18N3 [M + H]+ 300.1495; found 300.1498.
129.2, 129.3, 129.4, 131.2, 131.7 (J = 32 Hz), 141.8, 143.8, 151.4,
153.7, 154.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –62.68
(CF3) ppm. HRMS (ESI): calcd. for C20H15N3F3 [M + H]+
354.1213; found 354.1214.
7-Methyl-6-phenyl-4-(2-tolyl)-7H-pyrrolo[2,3-d]pyrimidine (6b): The
reaction was carried out by following general procedure C starting
6-(4-Methoxyphenyl)-7-methyl-4-(3-tolyl)-7H-pyrrolo[2,3-d]pyrimid-
from 4-chloropyrimidine 5a (150 mg, 0.62 mmol) and 2-tolylbor- ine (6f): The reaction was carried out by following general pro-
onic acid (87.9 mg, 0.65 mmol). The crude product was purified
by silica gel column chromatography (CH2Cl2/ethyl acetate, 8:2) to
cedure C starting from 4-chloropyrimidine 5b (150 mg, 0.55 mmol)
and 3-tolylboronic acid (78.2 mg, 0.58 mmol). The crude product
afford 6b (181.7 mg, 0.61 mmol, 99%) as a white solid. Rf = 0.45 was purified by silica gel column chromatography (CH2Cl2/ethyl
(CH2Cl2/ethyl acetate, 8:2); m.p. 104–106 °C (ethyl acetate). IR acetate, 8:2) to afford 6f (173.9 mg, 0.53 mmol, 96%) as an off-
(ATR diamond): ν = 2919, 2849, 1738, 1567, 1541, 1491, 1443,
white solid; m.p. 95–97 °C (ethyl acetate). Rf = 0.38 (CH2Cl2/ethyl
˜
1404, 1370, 1340, 1320, 1261, 1218, 1135, 1011, 935, 865, 787, 757,
acetate, 8:2). IR (ATR diamond): ν = 2921, 2855, 2153, 1968, 1615,
˜
748, 727, 699 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H),
1558, 1497, 1442, 1339, 1295, 1252, 1173, 1013, 893, 826, 786, 763,
3.91 (s, 3 H), 6.47 (s, 1 H), 7.27–7.40 (m, 3 H), 7.44–7.56 (m, 6 H), 700 cm–1. H NMR (300 MHz, CDCl3): δ = 2.59 (s, 3 H), 3.97 (s,
1
8.99 (s, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 20.3, 30.1,
99.9, 117.8, 125.8, 128.9, 129.0, 129.1, 129.2, 129.8, 131.1, 131.4,
136.6, 137.5, 142.8, 151.1, 152.9, 159.3 ppm. HRMS (ESI): calcd.
for C20H18N3 [M + H]+ 300.1495; found 300.1498.
3 H), 3.98 (s, 3 H), 6.92 (s, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.42 (d,
J = 7.5 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 2
H), 8.04–8.14 (m, 2 H), 9.11 (s, 1 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 21.7, 30.1, 55.5, 99.3, 114.4, 116.0, 123.8, 126.1, 128.7,
129.4, 130.6, 130.8, 138.4, 138.9, 142.9, 151.2, 153.3, 156.6,
160.3 ppm. HRMS (ESI): calcd. for C21H20N3O [M + H]+
330.1601; found 330.1602.
7-Methyl-6-phenyl-4-(4-tolyl)-7H-pyrrolo[2,3-d]pyrimidine (6c): The
reaction was carried out by following general procedure C starting
from 4-chloropyrimidine 5a (150 mg, 0.62 mmol) and 4-tolyl-
boronic acid (87.9 mg, 0.65 mmol). The crude product was purified
by silica gel column chromatography (CH2Cl2/ethyl acetate, 8:2) to
7-Methyl-4-(3-tolyl)-6-[4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]-
pyrimidine (6g): The reaction was carried out by following general
1520
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1514–1524

Microwave-Assisted Synthesis of Pyrrolo[2,3-d]pyrimidines
procedure C starting from 4-chloropyrimidine 5c (150 mg,
(63 MHz, CDCl3): δ = 21.7, 31.0, 55.2, 117.3, 128.5, 128.8, 129.7,
0.48 mmol) and 3-tolylboronic acid (68.7 mg, 0.51 mmol). The 130.9, 131.1, 131.3, 133.2, 139.6, 144.4, 151.1, 152.5, 160.5 ppm.
crude product was purified by silica gel column chromatography
(CH2Cl2/ethyl acetate, 8:2) to afford 6g (169.4 mg, 0.46 mmol,
96%) as an off-white solid. Rf = 0.43 (CH2Cl2/ethyl acetate, 8:2);
HRMS (ESI): calcd. for C20H17IN3 [M + H]+ 426.0462; found
426.0463.
5-Iodo-4-(4-methoxyphenyl)-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyr-
imidine (7d): The reaction was carried out by following general pro-
cedure D starting from diaryl pyrimidine 6d (150 mg, 0.48 mmol)
to afford 7d (209.1 mg, 0.48 mmol, 100%) as a yellow solid. Rf =
0.51 (CH2Cl2/ethyl acetate, 8:2); m.p. 196–198 °C (ethyl acetate).
m.p. 109–111 °C (ethyl acetate). IR (ATR diamond): ν = 2921,
˜
2849, 1615, 1551, 1440, 1322, 1160, 1114, 1068, 894, 847, 767,
1
702 cm–1. H NMR (300 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.87 (s,
3 H), 6.89 (s, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.41 (t, J = 7.6 Hz,
1 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.91 (d,
J = 7.6 Hz, 1 H), 7.95 (s, 1 H), 8.99 (s, 1 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 21.7, 30.3, 101.2, 115.8, 124.0 (J =
271 Hz), 125.9 (J = 4 Hz), 126.1, 128.8, 129.5, 129.6, 131.0 (J =
32 Hz), 131.1, 135.1, 138.1, 138.8, 141.1, 151.9, 153.6, 157.6 ppm.
19F NMR (376 MHz, CDCl3): δ = –62.73 (CF3) ppm. HRMS
(ESI): calcd. for C21H17N3F3 [M + H]+ 368.1369; found 368.1371.
IR (ATR diamond): ν = 2921, 2849, 1608, 1556, 1513, 1439, 1321,
˜
1
1293, 1243, 1174, 1025, 951, 885, 833, 797, 764, 739, 704 cm–1. H
NMR (300 MHz, CDCl3): δ = 3.77 (s, 3 H), 3.89 (s, 3 H), 7.04 (d,
J = 8.8 Hz, 2 H), 7.41–7.49 (m, 2 H), 7.50–7.58 (m, 3 H), 7.73 (d,
J = 8.8 Hz, 2 H), 8.96 (s, 1 H) ppm. 13C NMR (63 MHz, CDCl3):
δ = 31.0, 55.4, 55.5, 113.2, 117.2, 128.5, 128.8, 129.7, 130.9, 131.3,
132.7, 144.4, 151.1, 152.6, 160.0, 161.0 ppm. HRMS (ESI): calcd.
for C20H17IN3O [M + H]+ 442.0411; found 442.0412.
General Procedure D (Aryl Iodination): A solution of 6a–g
(1.0 mmol) and NIS (1.1 mmol) in acetonitrile (4.5 mL) was trans-
ferred to a microwave reaction tube and irradiated in a microwave
oven at 100 °C for 30 min. The progress of the reaction was moni-
tored by TLC. After cooling, the solvent was removed under vacuo.
Dichloromethane (20 mL) was added and the organic layer was
washed with aqueous saturated Na2S2O3 (2ϫ 16 mL), and NaOH
(10%, 2ϫ 16 mL). Evaporation of the solvent under reduced pres-
sure gave the crude product, which did not require further purifica-
tion.
5-Iodo-7-methyl-6-phenyl-4-[4-(trifluoromethyl)phenyl]-7H-pyrrolo-
[2.3-d]pyrimidine (7e): The reaction was carried out by following
general procedure D starting from diaryl pyrimidine 6e (150 mg,
0.42 mmol) to afford 7e (202.4 mg, 0.42 mmol, 99%) as a beige
solid. Rf = 0.60 (CH2Cl2/ethyl acetate, 8:2); m.p. 198–200 °C (ethyl
acetate). IR (ATR diamond): ν = 2922, 2852, 1733, 1557, 1476,
˜
1440, 1400, 1325, 1244, 1155, 1117, 1107, 1062, 1017, 948, 885,
1
843, 799, 762.704 cm–1. H NMR (400 MHz, CDCl3): δ = 3.79 (s,
3 H), 7.41–7.48 (m, 2 H), 7.51–7.59 (m, 3 H), 7.78 (d, J = 8.4 Hz,
2 H), 7.86 (d, J = 8.4 Hz, 2 H), 8.99 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 30.9, 54.4, 117.4, 124.2 (J = 272 Hz), 124.6
(J = 4 Hz), 128.8, 129.8, 130.7, 130.8, 131.3, 131.4 (J = 32 Hz),
139.4 (J = 1 Hz), 145.0, 151.0, 152.5, 158.5 ppm. 19F NMR
5-Iodo-7-methyl-6-phenyl-4-(3-tolyl)-7H-pyrrolo[2,3-d]pyrimidine
(7a): The reaction was carried out by following general procedure
D starting from diaryl pyrimidine 6a (500 mg, 1.67 mmol) to afford
7a (710.0 mg, 1.67 mmol, 100 %) as a yellow solid. Rf = 0.27
(CH2Cl2/ethyl acetate, 8:2); m.p. 188–190 °C (ethyl acetate). IR (376 MHz, CDCl3): δ = –62.52 (CF3) ppm. HRMS (ESI): calcd.
(ATR diamond): ν = 3045, 2913, 1547, 1439, 1402, 1330, 1254,
for C20H14F3IN3 [M + H]+ 480.0179; found 480.0180.
˜
1182, 1088, 1020, 958, 915, 783, 764, 708, 682 cm–1 1H NMR
.
5-Iodo-6-(4-methoxyphenyl)-7-methyl-4-(3-tolyl)-7H-pyrrolo[2,3-d]-
pyrimidine (7f): The reaction was carried out by following general
procedure D starting from diaryl pyrimidine 6f (150 mg,
0.46 mmol) to afford 7f (100%, 207.3 mg, 0.46 mmol) as a yellow
solid. Rf = 0.32 (CH2Cl2/acetone, 9:1); m.p. 179–181 °C (acetone).
(400 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.77 (s, 3 H), 7.32 (d, J =
7.6 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.43–7.47 (m, 2 H), 7.49–
7.61 (m, 5 H), 8.98 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.6, 30.9, 55.2, 117.3, 127.7, 128.2, 128.8, 129.7, 130.3, 130.9,
131.3, 131.8, 135.8, 137.3, 144.5, 151.1, 152.5, 160.5 ppm. HRMS
(ESI): calcd. for C20H17IN3 [M + H]+ 426.0462; found 426.0463.
IR (ATR diamond): ν = 2955, 2918, 2849, 1736, 1609, 1559, 1533,
˜
1467, 1446, 1414, 1289, 1243, 1173, 1021, 954, 837, 782, 711 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.77 (s, 3 H), 3.90
(s, 3 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.28–7.34 (m, 1 H), 7.35–7.43
(m, 3 H), 7.52–7.55 (m, 2 H), 8.96 (s, 1 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 21.6, 30.9, 55.2, 55.5, 114.2, 117.3, 123.2,
5-Iodo-7-methyl-6-phenyl-4-(2-tolyl)-7H-pyrrolo[2,3-d]pyrimidine
(7b): The reaction was carried out by following general procedure
D starting from diaryl pyrimidine 6b (150 mg, 0.5 mmol) to afford
7b (211.5 mg, 0.50 mmol, 99 %) as a yellow solid. Rf = 0.51
(CH2Cl2/ethyl acetate, 8:2); m.p. 185–187 °C (ethyl acetate). IR 127.7, 128.2, 130.2, 131.8, 132.3, 135.9, 137.3, 144.5, 150.9, 152.5,
(ATR diamond): ν = 2917, 2849, 1736, 1552, 1438, 1403, 1334,
160.2, 160.6 ppm. HRMS (ESI): calcd. for C21H19IN3O [M + H]+
456.0567; found 456.0566.
˜
1242, 1176, 1120, 1089, 951, 887, 796, 765, 725, 701 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 2.16 (s, 3 H), 3.79 (s, 3 H), 7.30–7.32 (m,
3 H), 7.37–7.41 (m, 1 H), 7.43–7.46 (m, 2 H), 7.50–7.54 (m, 3 H),
8.98 (s, 1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 20.3, 30.9,
54.9, 118.2, 125.3, 128.8, 129.7, 129.9, 130.0, 130.8, 130.9, 135.7,
136.6, 142.8, 136.9, 151.3, 152.0, 162.2 ppm. HRMS (ESI): calcd.
for C20H17IN3 [M + H]+ 426.0462; found 426.0463.
5-Iodo-7-methyl-4-(3-tolyl)-6-[4-(trifluoromethyl)phenyl]-7H-pyr-
rolo[2,3-d]pyrimidine (7g): The reaction was carried out by follow-
ing general procedure D starting from diaryl pyrimidine 6g
(150 mg, 0.41 mmol) to afford 7g (201.2 mg, 0.41 mmol, 100%) as
a beige solid. Rf = 0.53 (CH2Cl2/ethyl acetate, 7:3); m.p. 137–139 °C
(ethyl acetate). IR (ATR diamond): ν = 2923, 2855, 1736, 1555,
˜
5-Iodo-7-methyl-6-phenyl-4-(4-tolyl)-7H-pyrrolo[2,3-d]pyrimidine
(7c): The reaction was carried out by following general procedure
D starting from diaryl pyrimidine 6c (150 mg, 0.50 mmol) to afford
7c (212.3 mg, 0.50 mmol, 100%) as an off-white solid. Rf = 0.29
1447, 1407, 1320, 1251, 1163, 1127, 1067, 1017, 964, 911, 855, 791,
1
709 cm–1. H NMR (300 MHz, CDCl3): δ = 2.46 (s, 3 H), 3.79 (s,
3 H), 7.31–7.36 (m, 1 H), 7.38–7.45 (m, 1 H), 7.51–7.57 (m, 2 H),
7.61 (d, J = 8.7 Hz, 2 H), 7.82 (d, J = 8.7 Hz, 2 H), 9.01 (s, 1
(CH2Cl2/ethyl acetate, 8:2); m.p. 204–206 °C (ethyl acetate). IR H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5, 30.9, 55.8, 117.1,
(ATR diamond): ν = 2960, 2923, 2849, 1612, 1557, 1513, 1480,
123.8 (J = 274 Hz), 125.7 (J = 4 Hz), 127.7, 128.0, 130.4, 131.4,
131.6, 131.7 (J = 33 Hz), 134.8 (J = 1 Hz), 135.3, 137.3, 142.7,
˜
1459, 1441, 1335, 1287, 1243, 1224, 1177, 1033, 953, 827, 764,
1
703 cm–1. H NMR (250 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.77 (s, 151.2, 152.5, 160.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –62.82
3 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.39–7.49 (m, 2 H), 7.52–7.55 (m,
(CF3) ppm. HRMS (ESI): calcd. for C21H16F3IN3 [M + H]+
3 H), 7.65 (d, J = 7.8 Hz, 1 H), 8.97 (s, 1 H) ppm. 13C NMR 494.0336; found 494.0335.
Eur. J. Org. Chem. 2014, 1514–1524
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1521

G. Guillaumet, M. D. Pujol et al.
FULL PAPER
General Procedure E (Suzuki–Miyaura Coupling at C-5): Under ar-
and p-tolylboronic acid (35.2 mg, 0.26 mmol). The crude product
gon, a mixture of compound 7a–g (1.0 mmol), boronic acid was purified by silica gel column chromatography (CH2Cl2/acetone,
(1.05 mmol), sodium carbonate (2.0 mmol), and dichlorobis(tri-
phenylphosphine)palladium (0.05 mmol) in a degassed solvent mix-
ture of DME (3.8 mL) and H2O (0.6 mL) was transferred to a mi-
crowave reaction tube and irradiated in a microwave oven at 100 °C
for 60 min. The progress of the reaction was monitored by TLC.
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). Evaporation of the solvent under re-
duced pressure gave the crude product. A solution of the previous
residue and NIS (1.1 mmol) in acetonitrile (4.5 mL) was transferred
to a microwave reaction tube and irradiated in a microwave oven
at 100 °C for 30 min. The progress of the reaction was monitored
by TLC. After cooling, the solvent was removed, then dichloro-
methane (20 mL) was added and the organic layer was washed with
aqueous saturated Na2S2O3 (2 ϫ 16 mL) and NaOH (10 %, 2ϫ
16 mL). Evaporation of the solvent under reduced pressure gave
the crude product, which was purified by silica gel column
chromatography.
98:2 to 9:1) to afford 8c (64.8 mg, 0.17 mmol, 71%) as a dark-
beige solid (26% of starting material was also recovered). Rf = 0.23
(CH2Cl2/acetone, 9:1); m.p. 204–206 °C (acetone). IR (ATR dia-
mond): ν = 3034, 2917, 2849, 1737, 1553, 1537, 1516, 1436, 1413,
˜
1348, 1320, 1273, 1238, 1210, 1177, 1130, 1026, 962, 918, 892, 845,
1
816, 788, 763, 743, 710, 698 cm–1. H NMR (300 MHz, CDCl3): δ
= 2.00 (s, 3 H), 2.21 (s, 3 H), 3.82 (s, 3 H), 6.64 (d, J = 8.0 Hz, 2
H), 6.73 (d, J = 8.0 Hz, 2 H), 6.92–7.08 (m, 3 H), 7.24–7.31 (m, 3
H), 7.33–7.40 (m, 3 H), 9.01 (s, 1 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 21.2, 21.4, 30.3, 114.8, 115.2, 126.8, 127.7, 128.3,
128.7, 128.8, 129.6, 130.9, 131.0, 131.2, 131.3, 131.4, 135.8, 137.1,
137.5, 139.2, 151.2, 152.5, 159.7 ppm. HRMS (ESI): calcd. for
C27H24N3 [M + H]+ 390.1965; found 390.1964.
7-Methyl-6-phenyl-4,5-bis-(3-tolyl)-7H-pyrrolo[2,3-d]pyrimidine
(8d): The reaction was carried out by following general procedure
E starting from the iodo derivative 7a (100 mg, 0.24 mmol) and
m-tolylboronic acid (35.2 mg, 0.26 mmol). The crude product was
purified by silica gel column chromatography (CH2Cl2/acetone,
98:2 to 9:1) to afford 8d (69.6 mg, 0.18 mmol, 76%) as a white solid
(22% of starting material was also recovered). Rf = 0.09 (CH2Cl2/
5-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(3-tolyl)-7H-pyrrolo-
[2,3-d]pyrimidine (8a): The reaction was carried out by following
general procedure E starting from the iodo derivative 7a (100 mg,
0.24 mmol) and 4-methoxyphenylboronic acid (39.3 mg,
0.26 mmol). The crude product was purified by silica gel column
chromatography (CH2Cl2/acetone, 95:5) to afford 8a (83.9 mg,
0.21 mmol, 88%) as a white solid (8% starting material was also
recovered). Rf = 0.11 (CH2Cl2/acetone, 95:5); m.p. 144–146 °C
acetone, 9:1); m.p. 151–153 °C (acetone). IR (ATR diamond): ν =
˜
3028, 2919, 2847, 1557, 1538, 1492, 1463, 1441, 1418, 1349, 1324,
1241, 1193, 1166, 1128, 1086, 1025, 1000, 969, 924, 901, 870, 839,
1
812, 788, 763, 748, 719, 703 cm–1. H NMR (300 MHz, CDCl3): δ
= 1.93 (s, 3 H), 2.03 (s, 3 H), 3.82 (s, 3 H), 6.50 (s, 1 H), 6.60 (d, J
= 7.1 Hz, 1 H), 6.78–6.86 (m, 2 H), 7.01–7.04 (m, 3 H), 7.21–7.23
(m, 1 H), 7.26–7.32 (m, 2 H), 7.34–7.39 (m, 3 H), 9.02 (s, 1 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 21.1, 30.0, 114.7, 115.0, 126.5,
126.8, 127.3, 127.4, 127.7, 128.5, 128.7, 129.4, 130.7, 130.9, 131.1,
132.3, 133.7, 136.9, 137.6, 139.0, 151.1, 152.3, 159.7 ppm. HRMS
(ESI): calcd. for C27H24N3 [M + H]+ 390.1965; found 390.1967.
(acetone). IR (ATR diamond): ν = 2954, 1614, 1552, 1535, 1514,
˜
1466, 1438, 1413, 1349, 1322, 1287, 1238, 1176, 1134, 1108, 1036,
1
964, 919, 847, 816, 790, 762, 746 cm–1. H NMR (400 MHz, [D6]-
DMSO): δ = 1.96 (s, 3 H), 3.64 (s, 3 H), 3.73 (s, 3 H), 6.52 (d, J =
8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 6.88 (s, 1 H), 7.03–7.09 (m,
2 H), 7.21–7.27 (m, 1 H), 7.35–7.39 (m, 2 H), 7.39–7.43 (m, 3 H),
8.91 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 20.5,
29.6, 55.0, 112.9, 113.0, 114.2, 126.1, 126.2, 127.7, 128.3, 128.7,
129.1, 130.1, 130.8, 130.9, 131.6, 136.2, 137.0, 138.9, 150.6, 151.4,
157.6, 158.3 ppm. HRMS (ESI): calcd. for C27H24N3O [M + H]+
406.1914; found 406.1915.
7-Methyl-6-phenyl-4-(3-tolyl)-5-(2-tolyl)-7H-pyrrolo[2,3-d]pyrimid-
ine (8e): The reaction was carried out by following general pro-
cedure E starting from the iodo derivative 7a (100 mg, 0.24 mmol,
1.0 equiv.) and p-tolylboronic acid (35.2 mg, 0.26 mmol, 1.1 equiv.).
The product was purified by chromatography on silica gel (CH2Cl2/
acetone, 98:2 to 9:1) to afford starting material (82%). Product 8e
was not observed.
7-Methyl-6-phenyl-4-(3-tolyl)-5-[4-(trifluoromethyl)phenyl]-7H-pyr-
rolo[2,3-d]pyrimidine (8b): The reaction was carried out by follow-
ing general procedure E starting from the iodo derivative 7a
(100 mg, 0.24 mmol) and 4-trifluoromethylphenylboronic acid
(49.1 mg, 0.26 mmol). The crude product was purified by silica gel
column chromatography (CH2Cl2/acetone, 97.5:2.5 to 9:1) to afford
8b (69.8 mg, 0.16 mmol, 67%) as a beige solid (29% of starting
material was also recovered). Rf = 0.22 (CH2Cl2/acetone, 9:1); m.p.
5-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(2-tolyl)-7H-pyrrolo-
[2,3-d]pyrimidine (8f): The reaction was carried out by following
general procedure E starting from the iodo derivative 7b (100 mg,
0.24 mmol) and 4-methoxyphenylboronic acid (39.3 mg,
0.26 mmol). The crude product was purified by silica gel column
chromatography (CH2Cl2/acetone, 98:2 to 9:1) to afford 8f
(89.5 mg, 0.22 mmol, 94%) as a beige solid (5% of starting material
was also recovered). Rf = 0.42 (CH2Cl2/acetone, 9:1); m.p. 186–
199–201 °C (acetone). IR (ATR diamond): ν = 3043, 2921, 2847,
˜
1618, 1556, 1538, 1438, 1409, 1348, 1323, 1238, 1161, 1115, 1106,
188 °C (acetone). IR (ATR diamond): ν = 3060, 2997, 2931, 1609,
˜
1
1064, 1023, 962, 919, 856, 825, 789, 760, 711, 697 cm–1. H NMR
1559, 1513, 1415, 1349, 1319, 1287, 1243, 1224, 1179, 1121, 1033,
1
953, 894, 837, 809, 774, 763, 729, 701 cm–1. H NMR (400 MHz,
(400 MHz, CDCl3): δ = 1.98 (s, 3 H), 3.84 (s, 3 H), 6.85 (d, J =
8.0 Hz, 2 H), 6.90 (s, 1 H), 7.04 (d, J = 6.5 Hz, 2 H), 7.16 (d, J =
8.0 Hz, 2 H), 7.22 (d, J = 6.5 Hz, 1 H), 7.24–7.28 (m, 2 H), 7.39–
7.41 (m, 3 H), 9.04 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 20.9, 30.1, 113.2, 114.7, 124.2 (J = 4 Hz), 124.4 (J = 273 Hz),
126.4, 127.8, 128.1 (J = 32 Hz), 128.4, 128.8, 129.2, 129.8, 130.0,
130.9, 131.0, 131.1, 137.3, 138.1, 139.8, 151.5, 152.4, 159.6 ppm.
19F NMR (376 MHz, CDCl3): δ = –62.55 (CF3) ppm. HRMS
(ESI): calcd. for C27H21F3N3 [M + H]+ 444.1682; found 444.1683.
CDCl3): δ = 1.99 (s, 3 H), 3.65 (s, 3 H), 3.83 (s, 3 H), 6.34 (d, J =
8.6 Hz, 2 H), 6.55 (d, J = 8.6 Hz, 2 H), 6.94 (t, J = 7.4 Hz, 2 H),
7.01 (d, J = 7.4 Hz, 1 H), 7.09 (t, J = 7.4 Hz, 1 H), 7.26–7.28 (m,
2 H), 7.34–7.36 (m, 3 H), 9.00 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.8, 30.0, 55.2, 112.7, 114.4, 116.3, 125.1, 125.2,
128.3, 128.6, 128.7, 129.4, 129.7, 130.6, 131.1, 131.5, 135.8, 137.7,
138.9, 151.1, 151.8, 157.7, 160.1 ppm. HRMS (ESI): calcd. for
C27H24N3O [M + H]+ 406.1914; found 406.1913.
7-Methyl-6-phenyl-4-(3-tolyl)-5-(4-tolyl)-7H-pyrrolo[2,3-d]pyrimid- 5-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-(4-tolyl)-7H-pyrrolo-
ine (8c): The reaction was carried out by following general pro-
cedure E starting from the iodo derivative 7a (100 mg, 0.24 mmol)
[2,3-d]pyrimidine (8g): The reaction was carried out by following
general procedure E starting from the iodo derivative 7c (100 mg,
1522
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1514–1524

Microwave-Assisted Synthesis of Pyrrolo[2,3-d]pyrimidines
0.24 mmol) and 4-methoxyphenylboronic acid (39.3 mg,
0.26 mmol). The crude product was purified by silica gel column
chromatography (CH2Cl2/acetone, 98:2 to 9:1) to afford 8g
(61.9 mg, 0.15 mmol, 65%) as a beige solid (29% of starting mate-
rial was also recovered). Rf = 0.21 (CH2Cl2/acetone, 8:2); m.p. 157–
(ATR diamond): ν = 3033, 2921, 2850, 1738, 1612, 1541, 1519,
˜
1496, 1463, 1442, 1422, 1394, 1346, 1319, 1292, 1242, 1174, 1132,
1108, 1028, 961, 933, 917, 852, 835, 810, 798, 784, 741, 725,
1
709 cm–1. H NMR (300 MHz, CDCl3): δ = 2.04 (s, 3 H), 3.70 (s,
3 H), 3.81 (2s, 6 H), 6.48 (d, J = 8.9 Hz, 2 H), 6.66 (d, J = 8.9 Hz,
2 H), 6.89 (d, J = 8.9 Hz, 2 H), 7.00–7.06 (m, 3 H), 7.19 (d, J =
8.9 Hz, 2 H), 7.21–7.24 (m, 1 H), 8.99 (s, 1 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 21.1, 30.0, 55.3, 55.4, 113.0, 113.8, 114.0,
115.0, 122.7, 126.6, 126.7, 127.4, 129.3, 131.0, 131.9, 132.3, 137.0,
159 °C (acetone). IR (ATR diamond): ν = 2917, 2849, 1550, 1532,
˜
1510, 1462, 1440, 1418, 1346, 1321, 1290, 1237, 1174, 1132, 1110,
1035, 953, 892, 831, 800, 783, 767, 713, 704 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 2.27 (s, 3 H), 3.69 (s, 3 H), 3.81 (s, 3 H),
6.46 (d, J = 8.7 Hz, 2 H), 6.64 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 137.4, 138.9, 150.8, 152.2, 157.9, 159.1, 159.7 ppm. HRMS (ESI):
8.0 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.25–7.29 (m, 2 H), 7.32–
7.45 (m, 3 H), 9.00 (s, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 21.4, 29.9, 55.3, 113.0, 114.2, 115.0, 126.4, 128.0, 128.5, 128.6,
129.6, 130.7, 131.1, 131.9, 134.7, 138.5, 138.9, 151.0, 152.2, 158.0,
159.4 ppm. HRMS (ESI): calcd. for C27H24N3O [M + H]+
406.1914; found 406.1916.
calcd. for C28H26N3O2 [M + H]+ 436.2020; found 436.2020.
5-(4-Methoxyphenyl)-7-methyl-4-(3-tolyl)-6-[4-(trifluoromethyl)-
phenyl]-7H-pyrrolo[2,3-d]pyrimidine (8k): The reaction was carried
out by following general procedure E starting from the iodo deriva-
tive 7g (150 mg, 0.30 mmol) and 4-methoxyphenylboronic acid
(50.8 mg, 0.36 mmol). The crude product was purified by silica gel
4,5-Bis(4-methoxyphenyl)-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyr- column chromatography (CH2Cl2/acetone, 95:5) to afford 8k
imidine (8h): The reaction was carried out by following general pro-
cedure E starting from the iodo derivative 7d (100 mg, 0.23 mmol)
and 4-methoxyphenylboronic acid (37.9 mg, 0.25 mmol). The crude
product was purified by silica gel column chromatography
(84.5 mg, 0.18 mmol, 59%) as a white solid (34% of starting mate-
rial was also recovered). Rf = 0.39 (CH2Cl2/acetone, 7:3); m.p. 191–
193 °C (acetone). IR (ATR diamond): ν = 3055, 2955, 2923, 2854,
˜
1708, 1557, 1539, 1514, 1438, 1416, 1349, 1319, 1287, 1243, 1224,
(CH2Cl2/acetone, 98:2 to 9:1) to afford 8h (87.7 mg, 0.21 mmol, 1179, 1120, 1086, 1033, 953, 894, 837, 809, 773, 763, 722, 701 cm–1.
92%) as an off-white solid (6% of starting material was also reco-
vered). Rf = 0.39 (CH2Cl2/acetone, 8:2); m.p. 172–174 °C (acetone).
1H NMR (400 MHz, CDCl3): δ = 2.05 (s, 3 H), 3.71 (s, 3 H), 3.83
(s, 3 H), 6.51 (d, J = 8.8 Hz, 2 H), 6.65 (d, J = 8.8 Hz, 2 H), 6.96–
7.06 (m, 3 H), 7.21–7.25 (m, 1 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.63
(d, J = 8.0 Hz, 2 H), 9.02 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.1, 30.2, 55.3, 113.3, 115.0, 115.3, 124.0 (J =
274 Hz), 125.5 (J = 4 Hz), 125.9, 126.7, 127.5, 129.6, 130.4, 130.7,
IR (ATR diamond): ν = 3039, 2923, 2832, 1605, 1552, 1532, 1510,
˜
1455, 1435, 1416, 1347, 1322, 1301, 1289, 1246, 1235, 1173, 1130,
1
1108, 1034, 954, 927, 892, 842, 804, 783, 768, 704 cm–1. H NMR
(400 MHz, CDCl3): δ = 3.71 (s, 3 H), 3.74 (s, 3 H), 3.81 (s, 3 H),
6.50 (d, J = 8.8 Hz, 2 H), 6.59 (d, J = 8.8 Hz, 2 H), 6.67 (d, J = 131.0, 131.5, 131.9, 134.6 (J = 1 Hz), 137.1, 137.2, 151.6, 152.5,
8.8 Hz, 2 H), 7.24–7.29 (m, 4 H), 7.34–7.39 (m, 3 H), 8.98 (s, 1 158.3, 160.2 ppm. 19F NMR (376 MHz, CDCl3): δ = –62.73
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.0, 55.3, 55.4, 112.9,
113.1, 114.2, 114.8, 126.6, 128.5, 128.6, 130.2, 130.8, 131.2, 131.3,
132.0, 138.8, 151.1, 152.3, 158.1, 159.0, 160.3 ppm. HRMS (ESI):
calcd. for C27H24N3O2 [M + H]+ 422.1863; found 422.1864.
(CF3) ppm. HRMS (ESI): calcd. for C28H23F3N3O [M + H]+
474.1788; found 474.1787. CCDC-963176 contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
5-(4-Methoxyphenyl)-7-methyl-6-phenyl-4-[4-(trifluoromethyl)-
phenyl]-7H-pyrrolo[2,3-d]pyrimidine (8i): The reaction was carried
out by following general procedure E starting from the iodo deriva-
4-Chloro-5-(4-methoxyphenyl)-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]-
pyrimidine (9): The reaction was carried out by following general
tive 7e (100 mg, 0.21 mmol) and 4-methoxyphenylboronic acid procedure E starting from 10 (150 mg, 10a: 0.46 mmol or 10b:
(34.9 mg, 0.23 mmol). The crude product was purified by silica gel
column chromatography (CH2Cl2/acetone, 98:2 to 9:1) to afford 8i
(71.4 mg, 0.16 mmol, 74%) as a fluorescent yellow solid (20% of
starting material was also recovered). Rf = 0.5 (CH2Cl2/acetone,
0.41 mmol) and 4-methoxyphenylboronic acid (10a: 77.5 mg,
0.51 mmol or 10b: 68.4 mg, 0.45 mmol). The crude product was
purified by silica gel column chromatography (CH2Cl2/acetone,
95:5) to afford 9 as a white solid in 33% (53.5 mg, 0.15 mmol from
10a) and 70 % (99.2 mg, 0.28 mmol from 10b) yield. Rf = 0.35
(CH2Cl2/acetone, 95:5); m.p. 150–152 °C (acetone). IR (ATR dia-
8:2); m.p. 198–200 °C (acetone). IR (ATR diamond): ν = 3038,
˜
2935, 2832, 1612, 1557, 1513, 1484, 1470, 1442, 1406, 1349, 1318,
1290, 1246, 1232, 1172, 1158, 1119, 1104, 1064, 1037, 1017, 953,
mond): ν = 2931, 2836, 1541, 1515, 1479, 1445, 1414, 1286, 1247,
˜
926, 895, 846, 804, 780, 763, 748, 734, 703 cm–1
.
1H NMR
1234, 1220, 1178, 1155, 1124, 1028, 955, 892, 834, 750, 708,
1
(400 MHz, CDCl3): δ = 3.67 (s, 3 H), 3.84 (s, 3 H), 6.45 (d, J =
8.7 Hz, 2 H), 6.60 (d, J = 8.7 Hz, 2 H), 7.27–7.34 (m, 4 H), 7.36–
700 cm–1. H NMR (250 MHz, CDCl3): δ = 3.81 (s, 3 H), 3.83 (s,
3 H), 6.83 (d, J = 8.8 Hz, 2 H), 7.19 (d, J = 8.8 Hz, 2 H), 7.25–
7.40 (m, 5 H), 9.03 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 7.34 (m, 2 H), 7.36–7.45 (m, 3 H), 8.70 (s, 1 H) ppm. 13C NMR
= 30.1, 55.2, 113.2, 113.8, 115.6, 124.2 (J = 273 Hz), 124.2 (J =
(75.5 MHz, CDCl3): δ = 33.4, 55.3, 113.1, 113.9, 115.8, 124.6,
4 Hz), 125.8, 128.6, 128.9, 129.9, 130.3, 130.4 (J = 32 Hz), 131.0, 128.6, 128.9, 129.8, 130.8, 132.9, 140.0, 150.3, 151.7, 151.8,
131.8, 139.5, 141.1, 151.2, 152.3, 157.7, 158.4 ppm. 19F NMR
(376 MHz, CDCl3): δ = –62.70 (CF3) ppm. HRMS (ESI): calcd.
for C27H21F3N3O [M + H]+ 460.1631; found 460.1632.
158.7 ppm. HRMS (ESI): calcd. for C20H17ClN3O [M + H]+
350.1055; found 350.1055.
5-Bromo-4-chloro-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine
5,6-Bis(4-methoxyphenyl)-7-methyl-4-(3-tolyl)-7H-pyrrolo[2,3-d]pyr- (10a): A solution of 4-chloropyrimidine 5a (750 mg, 3.08 mmol)
imidine (8j): The reaction was carried out by following general pro-
cedure E starting from the iodo derivative 7f (100 mg, 0.22 mmol)
and 4-methoxyphenylboronic acid (36.7 mg, 0.24 mmol). The crude
product was purified by silica gel column chromatography
(CH2Cl2/acetone, 98:2 to 8:2) to afford 8j (54.6 mg, 0.13 mmol,
and NBS (639 mg, 3.59 mmol) in acetonitrile (5.5 mL) was trans-
ferred to a special microwave tube and irradiated in a microwave
oven at 100 °C for 30 min. The progress of the reaction was moni-
tored by TLC. After cooling, the solvent was removed under vacuo.
Dichloromethane (20 mL) was added and the organic layer was
57%) as a beige solid (40% of starting material was also recovered). washed with aqueous saturated Na2S2O3 (2ϫ 16 mL), and NaOH
Rf = 0.20 (CH2Cl2/acetone, 9:1); m.p. 195–197 °C (acetone). IR (10%, 2ϫ 16 mL). Evaporation of the solvent under reduced pres-
Eur. J. Org. Chem. 2014, 1514–1524
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1523

G. Guillaumet, M. D. Pujol et al.
FULL PAPER
Wang, C. Cherian, S. K. Desmoulin, S. Mitchell-Ryan, Z. Hou,
L. H. Matherly, A. Gangjee, J. Med. Chem. 2012, 55, 1758–
1770.
sure gave the crude product 10a (874.6 mg, 2.71 mmol, 87%) as a
yellow solid, which did not require further purification. Rf = 0.41
(CH2Cl2/ethyl acetate, 9:1); m.p. 168–170 °C (ethyl acetate). IR
[10] a) E. C. Taylor, B. Liu, J. Org. Chem. 2003, 68, 9938–9947; b)
CAS registration entry with query 4-X, 6-C, 5,7-H-pyrrolo[2,3-
d]pyrimidine: 1345 for X = N (January 2010).
(ATR diamond): ν = 3059, 2931, 1582, 1544, 1488, 1468, 1436,
˜
1347, 1221, 1174, 1152, 1028, 962, 890, 780, 762, 701 cm–1 1H
.
NMR (250 MHz, CDCl3): δ = 3.75 (s, 3 H), 7.47–7.58 (m, 5 H),
8.66 (s, 1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 30.9, 87.3,
115.3, 128.7, 129.0, 130.0, 130.6, 140.8, 150.9, 151.3, 151.8 ppm.
[11] a) Y. Liu, J. Fang, H. Cai, F. Xiao, K. Ding, Y. Hu, Bioorg.
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4-Chloro-5-iodo-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine
(10b): The reaction was carried out by following general procedure
D starting from 4-chloropyrimidine (5a) (300 mg, 1.23 mmol,
1.0 equiv.) to afford 10b (435.5 mg, 1.18 mmol, 96%) as a yellow
solid. Rf = 0.34 (CH2Cl2/ethyl acetate, 95:5); m.p. 203–205 °C (ethyl
acetate). IR (ATR diamond): ν = 3744, 3058, 2924, 2854, 1541,
˜
1479, 1434, 1343, 1265, 1217, 1168, 1026, 952, 886, 765, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.73 (s, 3 H), 7.41–7.47 (m, 2
H), 7.53–7.58 (m, 3 H), 8.64 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.4, 54.0, 117.5, 129.0, 130.1, 130.5, 130.8, 144.8,
150.6, 152.2, 152.4 ppm. HRMS (ESI): calcd. for C13H10ClIN3 [M
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Received: October 2, 2013
Published Online: January 8, 2014
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