Consecutive SNH and Suzuki-Miyaura cross-coupling reactions-an efficient synthetic strategy to pyrimidines bearing pyrrole and indole fragments

Article abstract of DOI:10.1002/ejoc.201201035

The combination of the Suzuki-Miyaura cross-coupling and nucleophilic aromatic substitution of hydrogen reactions is a versatile tool for the syntheses of 4-(1R-pyrrol-2-yl)-and 4-(1R-indol-3-yl)-5-(hetero)aryl-substituted pyrimidines from commercially available 5-bromopyrimidine. The S _N^H [AE, (addition-elimination)] and S_N ^H [AO, (addition-oxidation)] reactions of 5-bromopyrimidine with pyrroles and indoles were studied by gas chromatography-mass spectrometry. The structures of the intermediate σ^H adducts as well as the pyrrole-(hetero)arylpyrimidine and indole-(hetero)arylpyrimidine dyads were established for the first time by X-ray crystal structure analysis.

Full text of DOI:10.1002/ejoc.201201035

FULL PAPER
DOI: 10.1002/ejoc.201201035
H
Consecutive SN and Suzuki–Miyaura Cross-Coupling Reactions – an Efficient
Synthetic Strategy to Pyrimidines Bearing Pyrrole and Indole Fragments
Egor V. Verbitskiy,*[a] Gennady L. Rusinov,[a,b] Valery N. Charushin,[a,b]
Oleg N. Chupakhin,[a,b] Ekaterina M. Cheprakova,[a] Pavel A. Slepukhin,[a]
Marina G. Pervova,[a] Marina A. Ezhikova,[a] and Mikhail I. Kodess[a]
Keywords: Synthetic methods / Cross-coupling / Nucleophilic substitution / Nitrogen heterocycles / Microwave chemistry
The combination of the Suzuki–Miyaura cross-coupling and
nucleophilic aromatic substitution of hydrogen reactions is a
versatile tool for the syntheses of 4-(1R-pyrrol-2-yl)- and 4-
(1R-indol-3-yl)-5-(hetero)aryl-substituted pyrimidines from
reactions of 5-bromopyrimidine with pyrroles and indoles
were studied by gas chromatography–mass spectrometry.
The structures of the intermediate σH adducts as well as the
pyrrole-(hetero)arylpyrimidine and indole-(hetero)arylpyrim-
idine dyads were established for the first time by X-ray crys-
tal structure analysis.
H
commercially available 5-bromopyrimidine. The SN [AE,
H
(addition–elimination)] and SN [AO, (addition–oxidation)]
Introduction
Transition-metal-catalyzed cross-coupling reactions are
now recognized as one of the most powerful synthetic tools
for carbon–carbon bond formations. The palladium-cata-
lyzed coupling of aryl halides or their synthetic equivalents,
such as aryl triflates, with aryl metal compounds (Ar–M,
M = Mg, Zn, B, Sn, Si, etc.) are quite often exploited for
the syntheses of biaryl molecules, whose skeletons are found
in a wide range of important compounds including natural
products and organic functional materials (see
Scheme 1).[1–3] In particular, the Suzuki–Miyaura cross-
coupling reactions of aryl halides with organoboronic acids
[M = B(OH)2] proved to be a versatile approach for the
selective formation of carbon–carbon bonds.[4]
Another synthetic methodology to form the C–C and C–
X (X is a heteroatom) bonds is based on the nucleophilic
aromatic substitution of hydrogen (SNH, see Scheme 1).[5]
The advantage of this approach is that it requires neither
the presence of a halogen atom in the aromatic substrate
nor an expensive metal catalyst.
Scheme 1.
notic, antitumor, antiviral, and antimicrobial activities.[7]
On the other hand, pyrrole and indole derivatives are part
of the many natural compounds and synthetic drugs that
demonstrate a wide range of biological activities.[7,8] Thus,
the syntheses of polycyclic systems bearing the pyrimidine
ring and pyrrole or indole substituents are of interest for
medicinal chemistry. In particular, 4-(1-methyl-1H-pyrrol-2-
yl)pyrimidine[9] and 3-(pyrimidin-4-yl)-1H-indole[10] are the
simplest representatives of these heterocyclic systems, which
were obtained previously and utilized for further transfor-
mations. However, it should be noted that general synthetic
methods enabling one to modify the aryl substituents on
the pyrimidine core have not been described in the litera-
ture.
In this communication, we report a new and convenient
approach to (pyrrol-2-yl)- and (indol-3-yl)-substituted pyr-
imidines by using a combination of two C–C coupling reac-
tions, that is, the microwave-assisted palladium-catalyzed
Suzuki–Miyaura cross-coupling reaction and the nucleo-
philic aromatic substitution of hydrogen.
Pyrimidines belong to an important class of heteroarom-
atic compounds that have found wide applications as effec-
tive pharmaceuticals, agrochemicals, and organic materi-
als.[6] A number of pyrimidines are known to exhibit hyp-
[a] I. Postovsky Institute of Organic Synthesis, Ural Branch,
Russian Academy of Sciences,
S. Kovalevskoy Str. 20, Ekaterinburg 620041, Russian
Federation
E-mail: Verbitsky@ios.uran.ru
Homepage: www.ios.uran.ru
[b] Ural Federal University, named after the First President of
Russia, B. N. Yeltsin,
Mira Str. 19, Ekaterinburg 620002, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201035.
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H
Consecutive SN and Suzuki–Miyaura Cross-Coupling Reactions
Table 1. Effects of the reaction conditions on structure and yields
Results and Discussion
of SN products 4a, 4b, 5a, 5b, 8a, 8b, 9a, and 9b derived from σH
H
adducts 3a, 3b, 7a, and 7b.
It has previously been shown that pyrimidine, 5-methyl-
pyrimidine, and their benzannulated analogs react with a
number of aromatic compounds, such as phenols, pyrroles,
indoles, and thiophenes, in the presence of trifluoroacetic
acid to form rather stable 4-aryl-substituted 3,4-dihydropyr-
imidinium salts.[11] In addition, we have used the combina-
tion of the Suzuki-Miyaura cross-coupling reaction and nu-
cleophilic aromatic substitution of hydrogen (SNH) in the
synthesis of a series of 4,5-di(thiophen-2-yl)-substituted
pyrimidines.[12]
It has been established that the reactions of pyrrole and
indole derivatives with 5-bromopyrimidine (1) in
CF3COOH lead to rather complex multicomponent mix-
tures (on the basis of TLC and GC–MS data). However,
the use of boron trifluoride diethyl etherate (BF3·Et2O) as
a Lewis acid in the reactions of 1 with pyrrole (2a) and N-
methylpyrrole (2b) in methanol resulted in the formation
of 5-bromo-4-(1-R-1H-pyrrol-2-yl)-3,4-dihydropyrimidin-1-
ium tetrafluoroborates 3a and 3b in good yields (55–75%,
see Scheme 2).
H
Entry σH Ad- Reaction conditions
Time
[h]
SN
Isol. Reaction
duct
product yield mixtures
[%] [%][a]
1
3a
K3Fe(CN)6/KOH/H2O
2
4a
50
4a (62)
5a (25)
impurities
(13)
2
3
4
3b
3a
3b
K3Fe(CN)6/KOH/H2O
piperidine
2
4b
5a
5b
52
25
35
4b (76)
impurities
(24)
5a (50)
impurities
(50)
24
24
piperidine
5b (57)
4b (3)
3b (6)
impurities
(34)
5
7a
K3Fe(CN)6/KOH/H2O
2
8a
40
8a (61)
1 (8)
6a (12)
9a (17)
impurities
(2)
6
7
8
7b
7a
7b
K3Fe(CN)6/KOH/H2O
piperidine
2
8b
9a
9b
40
23
51
8b (59)
1 (9)
6b (25)
impurities
(7)
9a (37)
1 (22)
6a (35)
impurities
(6)
24
24
piperidine
9b (63)
6b (6)
9a (12)
impurities
(19)
Scheme 2.
[a] To study the reaction mixtures, the solvent was removed by dis-
tillation, and the residue was analyzed by GC–MS.
Dihydropyrimidines 3a and 3b appear to be intermediate
H
σH adducts of the SN reaction and, indeed, they can be
The unequivocal evidence for the structures of the substi-
H
H
transformed into SN products 4 and 5. Using K3Fe(CN)6/ tuted dihydropyrimidines and the final SN products, in
KOH as the oxidative system enabled us to transform dihy- particular for 5-bromo-4-(1-methyl-1H-pyrrol-2-yl)-3,4-di-
dropyrimidines 3a and 3b into the products of a nucleo- hydropyrimidinium tetrafluoroborate (3b) and 5-bromo-4-
philic aromatic substitution of hydrogen Ϫ 5-bromo-4-(1- (1H-pyrrol-2-yl)pyrimidine (4a), has been obtained by X-
R-1H-pyrrol-2-yl)pyrimidines 4a and 4b. The reaction pro- ray crystal structure analysis (see Supporting Information,
ceeded through the classic two-step “addition–oxidation” Figures S1 and S2).
H
SN pathway (AO).[5a] On the contrary, in the presence of
The reactions of 1 with indoles have been shown to occur
secondary amines, aromatization of compounds 3a and 3b in a similar manner. Indeed, in methanol, 5-bromopyrimid-
took place, because of the elimination of HBr, thus yielding ine (1) in the presence of boron trifluoride diethyl etherate
4-(1H-pyrrol-2-yl)- and 4-(1-methyl-1H-pyrrol-2-yl)-substi- (BF3·Et2O) underwent reaction with indole (6a) or N-ethyl-
tuted pyrimidines 5a and 5b, respectively, as products of the indole (6b) to afford the corresponding 5-bromo-4-(1-R-
cine substitution of hydrogen (see Scheme 2 and Table 1). It 1H-indol-3-yl)-3,4-dihydropyrimidin-1-ium tetrafluorobor-
was shown previously that the cine substitution of hydro- ates 7a and 7b in moderate yields (50–65%, see Scheme 3).
H
gen, in the case of dihydropyrimidines, proceeds better in The SN (AO) products, 3-(5-bromopyrimidin-4-yl)-1-R-
H
piperidine.[12] Using an oxidant for the SN cine substitu- 1H-indoles 8a and 8b were obtained by using K3Fe(CN)6/
H
tion reactions was unnecessary, as it has been proved unam- KOH in water, whereas the SN cine substitution products,
biguously that these reactions can be carried out under inert 1-R-3-pyrimidin-4-yl-1H-indoles 9a and 9b, were formed in
oxygen-free conditions.
the presence of piperidine (see Scheme 3 and Table 1). The
Eur. J. Org. Chem. 2012, 6612–6621
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E. V. Verbitskiy et al.
FULL PAPER
H
structures of the SN (AO) products 8a and 8b were con- Table 2. The microwave-assisted Suzuki–Miyaura cross-coupling
reaction of 5-bromo-4-aryl-substituted pyrimidines 4b and 8b with
firmed by X-ray crystal structure analysis (see Supporting
Information, Figures S3 and S4).
3-nitrophenylboronic acid (10).
Entry Pyrimidine Isolated yield [%] Reaction mixtures [%][a]
1
4b
11b (58)
11b (4)
1 (2)
Ph3PO (92)
impurities (50)
12b (15)
2
8b
12b (70)
9b (47)
Ph3PO (29)
impurities (9)
[a] Analyzed by GC–MS.
with pyrroles 2a and 2b and indoles 6a and 6b were eluci-
dated. Compounds 15–17 were obtained in high yields by
using a similar cross-coupling procedure under microwave
activation at 155 °C in THF (tetrahydrofuran)/H2O (3:4, see
Scheme 5).
Scheme 3.
The bromo compounds 4a, 4b, 8a, and 8b were further
treated with 3-nitrophenylboronic acid (10) under micro-
wave irradiation (MW, 155 °C, 10 min) in a Suzuki–Mi-
yaura cross-coupling reaction. The reaction of pyrimidines
4b and 8b with boronic acid 10 resulted in the formation
of 4-(1-methyl-1H-pyrrol-2-yl)-5-(3-nitrophenyl)pyrimidine
(11b) and 1-ethyl-3-[5-(3-nitrophenyl)pyrimidin-4-yl]-1H-in-
dole (12b) in good yields (see Scheme 4 and Table 2). Un-
fortunately, under the same conditions, the reaction of pyr-
imidines 4a and 8a with boronic acid gave the 4,5-disubsti-
tuted pyrimidines 11a and 12a, respectively, in only trace
amounts (approximately 1%), measured by GC–MS. Com-
pounds 11a and 12a were not isolated.
Scheme 5.
Pyrimidines 15–17 were then involved in the reactions
with pyrroles 2a and 2b and indoles 6a and 6b in MeOH in
the presence of BF3·Et2O. The resulting reaction mixtures
were stirred at room temperature for 24 h. After that time,
the solvent was removed, and the corresponding 1,2-dihy-
dropyrimidines I or II, without any further purification,
were oxidized with K3Fe(CN)6 in an aqueous solution
KOH for the appropriate time (see Scheme 6 and Table 3).
The reaction mixtures were analyzed by GC–MS, and the
4,5-di(hetero)aryl-substituted pyrimidines 11, 12, and 18–21
were obtained only in moderate yields, apparently, because
of side reactions followed by the oxidation of intermediate
σH adducts I and II. As the yields (GC–MS data) of 3-[5-
(3-nitrophenyl)pyrimidin-4-yl]-1H-indole (12a), 3-[5-(thio-
phen-2-yl)pyrimidin-4-yl]-1H-indole (20a), and 3-[5-(thio-
phen-3-yl)pyrimidin-4-yl]-1H-indole (21a) were low (see
Table 3, Entries 7, 9, and 11,), the corresponding SNH prod-
ucts were not isolated. However, the structure of 4-(1H-pyr-
rol-2-yl)-5-thiophen-2-yl-pyrimidine (18a) was confirmed
Scheme 4.
It is worth nothing that the described method above for by X-ray crystal structure analysis (see Supporting Infor-
obtaining 4-(pyrrole-2-yl)-5-aryl- and 4-(indol-3-yl)-5-aryl- mation, Figure S5).
substituted pyrimidines, 11 and 12, respectively, is not a
With regard to all of the synthesized pyrrolyl-pyrimid-
unique one and can be complemented with an inverted se- ines (i.e., 3a, 4a, 5a, 11a, 18a, and 19a) with an unsubsti-
H
quence of SN and cross-coupling reactions.
tuted nitrogen in the pyrrole ring, we noted an interesting
1
To realize this, we first obtained 5-(3-nitrophenyl)pyrim- feature in their H NMR spectra. The NH protons give a
idine (15). In addition, to show the synthetic potential of broadened singlet, the half linewidth of which varies from
H
this sequence of SN and cross-coupling reactions, 5-(thio- 20 to 50 Hz. Taking this into account, it is unlikely to ex-
phen-2-yl)pyrimidine (16) and 5-(thiophen-3-yl)pyrimidine pect the appearance of coupling between the NH proton
H
(17) were obtained, and their reactivity in SN reactions and CH protons in the pyrrole ring. Therefore the expected
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H
Consecutive SN and Suzuki–Miyaura Cross-Coupling Reactions
Scheme 6.
Table 3. Reaction of 5-(hetero)arylpyrimidines 15–17 with pyrroles signals was observed in the 1H NMR spectra of compounds
2a and 2b and indoles 6a and 6b. Composition of the reaction mix-
3a, 4a, 5a, 11a, 18a, and 19a, which was because of the
tures and yields of 4,5-di(hetero)aryl-substituted pyrimidines 11,
coupling with the NH proton. It was confirmed by a
12, and 18–21.
1H{1H} double-resonance experiment, in which the simpli-
Entry Reactants Oxidation
conditions
Time [h] Reaction mixtures
[%][a]
Isolated
yield [%]
fication of the splitting patterns was observed as the NH
resonance was irradiated (see Figure 1). The measured val-
ues of the coupling constants turned out to be approxi-
1
2
3
15 + 2a
15 + 2b
16 + 2a
room temp.
room temp.
room temp.
2
2
11a (39)
impurities (61)
11b (59)
11a (36)
11b (55)
18a (42)
4
4
3
mately the same, that is, JNH,H(3Ј) ≈ JNH,H(4Ј) ≈ JNH,H(5Ј)
,
and were in the range of 2.5–2.7 Hz.
impurities (41)
18a (69)
24
16 (23)
impurities (8)
18b (89)
impurities (11)
19a (77)
4
5
16 + 2b
17 + 2a
room temp.
room temp.
24
24
18b (38)
19a (54)
17 (13)
impurities (10)
19b (68)
17 (5)
impurities (27)
12a (2)
6
7
17 + 2b
15 + 6a
room temp.
room temp.
24
2
19b (51)
12a[b]
15 (46)
6a (50)
impurities (2)
12b (52)
6b (21)
impurities (27)
20a (45)
1
Figure 1. Multiplets of the pyrrole protons in the H NMR spec-
trum (500 MHz, CDCl3) of compound 11a. The regular (bottom)
and the NH decoupled (top) spectra.
8
9
15 + 6b
room temp.
room temp.
24
24
12b (33)
16 + 6a
20a[b]
16 (21)
6a (29)
impurities (5)
20b (4)
6b (94)
impurities (2)
21a (26)
17 (28)
6a (29)
impurities (17)
21b (12)
Conclusions
10
11
16 + 6b
reflux
2
20b (15)
H
The tandem cross-coupling and SN reactions have been
shown to be a versatile tool for the syntheses of pyrimidines
bearing pyrrole and indole fragments. The X-ray crystal
structure data for a number of bromo- and (hetero)aryl-
substituted pyrimidines provide unequivocal evidence for
the suggested structures.
17 + 6a
room temp.
24
21a[b]
12
17 + 6b
reflux
2
21b (13)
6b (80)
impurities (8)
[a] Reaction mixtures analyzed by GC–MS after oxidation with
K3Fe(CN)6. [b] The product was not isolated.
Experimental Section
General Methods: The solvents and reagents were dried and puri-
fied according to the described procedures.[13]The starting 5-
bromopyrimidine (1), pyrrole (2a), N-methylpyrrole (2b), and in-
multiplicity of the CH proton signal should be a double
doublet because of the JH,H and JH,H coupling constants.
3
4
However, additional splitting from all of the pyrrole proton dole (6a) were purchased from Sigma–Aldrich and used without ad-
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E. V. Verbitskiy et al.
FULL PAPER
ditional purification. N-Ethylindole was prepared according to a
reported method.[14] The solvents (THF and H2O) used for the
microwave-assisted Suzuki cross-coupling reaction were deoxy-
genated by bubbling argon through them for 1 h. 1H and 13C NMR
spectroscopic data were recorded with Bruker DRX-400 and AV-
ANCE-500 instruments, using Me4Si as an internal standard. All
of the signals in the 1H and 13C NMR spectra were assigned on
the basis of 2D 1H–1H COSY, 1H–13C HSQC (heteronuclear single
quantum correlation), and HMBC experiments. Elemental analyses
were carried with a Eurovector EA 3000 automated analyzer. Melt-
ing points were measured using a Boetius with combined heating
stages. The GC–MS analyses of all of the samples were carried out
with an Agilent GC 7890A MS 5975C Inert XL EI/CI GC–MS
spectrometer, using a quadrupole mass spectrometric detector with
electron ionization (70 eV) and a quartz capillary column HP-5MS
(30 mϫ0.25 mm, film thickness, 0.25 mm), and scanned over the
total ionic current in the range m/z 20–1000. Helium served as the
carrier gas, and the split ratio of the flow was 1:50. The consump-
tion through the column was 1.0 mLmin–1. The initial temperature
of the column was 40 °C (storage 3 min), and the programming
rate was 10 °Cmin–1 to 290 °C (storage 20 min). The temperatures
of the evaporator and the source were 250 and 230 °C, respectively,
and the temperatures of the quadrupole and the transition chamber
were 150 and 280 °C, respectively. Solutions of the samples were
prepared in acetonitrile with a concentration of 3–4 mgmL–1, and
1-mL samples of the obtained solutions were analyzed. Column
chromatography was carried out using Lancaster silica gel 0.040–
0.063 mm (230–400 mesh), eluting with ethyl acetate/hexane (1:2).
The progress of reactions and the purity of compounds were
checked by TLC on Sorbfil plates (Russia), and the spots were visu-
alized by UV light (λ = 254 or 365 nm). Microwave experiments
were carried out with a Discover unimodal microwave system
(CEM, USA) with a working frequency of 2.45 GHz, and the
power of the microwave radiation ranged from 0 to 300 W. The
reactions were carried out in a 10-mL reaction tube with a hermetic
Teflon® stopper. The temperature of the reaction was monitored
using an IR sensor inserted through the external surface of the
reaction vessel. X-Ray crystal structure data were collected with an
Xcalibur CCD diffractometer, using Mo-Kα (λ = 0.71069 Å) radia-
tion at T = 295(2) K. The crystal data and data collection param-
eters are summarized in Table S4 (see Supporting Information).
Unit cell parameters were refined using all of the collected spots
after the integration process. The details of the refinement and the
final R indices are presented in Table S4.
5-Bromo-4-(1H-pyrrol-2-yl)-3,4-dihydropyrimidine (3a): Pale green
crystalline powder (122 mg, 54%); m.p. 141–142 °C (decomp). H
1
NMR (500 MHz, CD3CN): δ = 5.28 (s, 1 H, 6-H), 6.02–6.04 (m, 2
H, 4Ј-H and 3Ј-H), 6.3–6.9 (br. s, NH, H2O) 6.56 (s, 1 H, 4-H),
6.69 (td, J = 2.6, 1.7 Hz, 1 H, 5Ј-H), 7.01 (s, 1 H, 2-H), 9.24 (br. s,
1 H, NH) ppm. 13C NMR (126 MHz, CD3CN): δ = 57.08, 102.03
(br. s), 107.82, 109.23, 119.43, 131.26 (br. s), 135.08, 144.87 ppm.
C8H8BrN3 (226.08): calcd. C 42.50, H 3.57, N 18.59, Br 35.34;
found C 42.55, H 3.43, N 18.49, Br 35.53.
5-Bromo-4-(1-methyl-1H-pyrrol-2-yl)-3,4-dihydropyrimidin-1-ium
Tetrafluoroborate (3b): Pale yellow powder (239 mg, 73%); m.p.
143–145 °C. 1H NMR (500 MHz, CD3CN): δ = 3.66 (s, 3 H,
NCH3), 5.66 (s, 1 H, 4-H), 6.09 (dd, J = 3.7, 2.9 Hz, 1 H, 4Ј-H),
6.25 (dd, J = 3.7, 1.8 Hz, 1 H, 3Ј-H), 6.72 (t, J = 2.3 Hz, 1 H, 5Ј-
H), 6.75 (s, 1 H, 6-H), 7.91 (s, 1 H, 2-H), 8.41 (br. s, 2 H, NH-3
and NH-1) ppm. 13C NMR (126 MHz, CD3CN): δ = 34.96
(NCH3), 53.23 (C-4), 106.62 (C-5), 109.19 (C-4Ј), 112.95 (C-3Ј),
122.83 (C-6), 126.61 (C-5Ј), 130.76 (C-2Ј), 148.62 (C-2) ppm.
C9H11BBrF4N3 (327.92): calcd. C 32.97, H 3.38, N 12.81; found C
33.00, H 3.24, N 12.79.
CCDC-881598 (for 3b), -881597 (for 4a), -881599 (for 8a), -881600
(for 8b), and -881601 (for 18a) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for the Syntheses of the σH Adducts
5-Bromo-4-(1H-indol-3-yl)-3,4-dihydropyrimidin-1-ium Tetrafluoro-
borate (7a): Dark red oil (240 mg, 66%). 1H NMR (500 MHz,
5-Bromo-4-(1-R-1H-pyrrol-2-yl)-3,4-dihydropyrimidin-1-iums and 5- CD3CN): δ = 5.81 (dd, J = 1.9, 1.1 Hz, 1 H, 4-H), 6.76 (dm, J =
Bromo-4-(1-R-1H-indol-3-yl)-3,4-dihydropyrimidin-1-iums
Tetra-
4.8 Hz, 1 H, 6-H), 7.15 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, 5Ј-H), 7.22
(ddd, J = 8.1, 7.0, 1.2 Hz, 1 H, 6Ј-H), 7.43 (d, J = 2.7 Hz, 1 H, 2Ј-
H), 7.52 (dm, J = 8.1 Hz, 1 H, 7Ј-H), 7.58 (dm, J = 8.0 Hz, 1 H,
4Ј-H), 7.95 (t, J = 5.8 Hz, 1 H, 2-H), 8.58 (br. s, 1 H, NH-3), 9.27
(br. s, 1 H, NH-1), 9.67 (br. s, 1 H, NH-1Ј) ppm. 13C NMR
(126 MHz, CD3CN): δ = 54.64 (C-4), 107.68 (C-5), 113.86 (C-7Ј),
114.23 (C-3Ј), 119.59 (C-4Ј), 121.82 (C-5Ј), 122.72 (C-6), 124.02 (C-
6Ј), 126.22 (C-3Јa), 127.8 (C-2Ј), 138.31 (C-7Јa), 148.8 (C-2) ppm.
C12H11BBrF4N3 (363.95): calcd. C 39.60, H 3.05, N 11.55; found
C 39.97, H 2.27, N 11.57.
fluoroborates 3a, 3b, 7a, and 7b: To a stirred mixture of 5-bromo-
pyrimidine (1, 159 mg, 2.0 mmol) and compound 2a, 2b, 6a, or 6b
(2.0 mmol) in MeOH (3 mL) was added BF3·Et2O (1.1 mmol). The
reaction mixture was stirred at room temperature for 24 h, and the
solvent was evaporated. In general, after removal of the solvent
under reduced pressure, the residue was washed with ethyl acetate
or Et2O and then with CHCl3. However, in the case of compound
3a, the residue was preliminarily washed with aqueous Na2CO3 and
then with MeCN.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6612–6621

H
Consecutive SN and Suzuki–Miyaura Cross-Coupling Reactions
GC: tR = 18.79 min. MS: m/z (%) = 237 (100) [M]+ for 79Br, 239
(100) [M]+ for 81Br.
5-Bromo-4-(1-ethyl-1H-indol-3-yl)-3,4-dihydropyrimidin-1-ium Tet-
rafluoroborate (7b): Pink powder (188 mg, 48%); m.p. 162–163 °C.
1H NMR (500 MHz, CD3CN): δ = 1.42 (t, J = 7.2 Hz, 3 H, CH3),
4.22 (q, J = 7.2 Hz, 2 H, NCH2), 5.84 (d, J = 1.0 Hz, 1 H, 4-H),
6.79 (s, 1 H, 6-H), 7.17 (ddd, J = 8.0, 7.1, 1.1 Hz, 1 H, 5Ј-H), 7.28
(ddd, J = 8.2, 7.1, 1.1 Hz, 1 H, 6Ј-H), 7.45 (s, 1 H, 2Ј-H), 7.50 (dm,
J = 8.2 Hz, 1 H, 7Ј-H), 7.58 (dm, J = 8.0 Hz, 1 H, 4Ј-H), 7.95 (s,
1 H, 2-H), 8.53 (br. s, 1 H, NH), 9.19 (br. s, 1 H, NH) ppm. 13C
NMR (126 MHz, CD3CN): δ = 16.16 (CH3), 42.44 (NCH2), 54.55
(C-4), 107.71 (C-5), 112.02 (C-7Ј), 113.47 (C-3Ј), 119.95 (C-4Ј),
121.72 (C-5Ј), 122.68 (C-6), 123.78 (C-6Ј), 126.99 (C-3Јa), 130.30
(C-2Ј), 138.02 (C-7Јa), 148.79 (C-2) ppm. C14H15BBrF4N3 (392.00):
calcd. C 42.90, H 3.86, N 10.72; found C 43.10, H 3.73, N 10.63.
3-(5-Bromopyrimidin-4-yl)-1H-indole (8a): See Table 1, Entry 5.
Pale beige powder; m.p. 238–240 °C. 1H NMR (400 MHz,
CD3CN): δ = 7.22–7.30 (m, 2 H, 5Ј-H and 6Ј-H), 7.55 (dm, J =
8.0 Hz, 1 H, 7Ј-H), 8.52 (dm, J = 8.0 Hz, 1 H, 4Ј-H), 8.59 (d, J =
3.1 Hz, 1 H, 2Ј-H), 8.84 (s, 1 H, 6-H), 9.07 (s, 1 H, 2-H), 9.96 (br.
s, 1 H, NH) ppm. 13C NMR (126 MHz, CD3CN): δ = 113.31 (C-
7Ј), 113.57 (C-3Ј), 117.88 (C-5), 122.72 (C-5Ј), 124.03 (C-4Ј), 124.46
(C-6Ј), 127.91 (C-3Јa), 132.24 (C-2Ј), 137.72 (C-7Јa), 157.74 (C-2),
161.05 (C-6), 161.08 (C-4) ppm. C12H8BrN3 (274.12): calcd. C
52.58, H 2.94, N 15.33; found C 52.55, H 3.03, N 15.49. GC: tR
=
26.38 min. MS: m/z (%) = 273 (100) [M]+ for 79Br, 275 (100) [M]+
for 81Br.
General Procedure for the Syntheses of 5-Bromo-4-(hetero)aryl-Sub-
stituted Pyrimidines 4a, 4b, 8a, and 8b: Compound 3a, 3b, 7a, or
7b (0.5 mmol) was added to solution of KOH (112 mg, 2.0 mmol,
4 equiv.) and K3Fe(CN)6 (329 mg, 1.0 mmol, 2 equiv.) in water
(5 mL). The resulting mixture was stirred at room temperature for
2 h. The precipitate was removed by filtration, washed with H2O,
and then air dried. The residue was purified by flash column
chromatography (hexane/ethyl acetate, 1:2) to afford the desired
H
SN product 4a, 4b, 8a, or 8b.
3-(5-Bromopyrimidin-4-yl)-1-ethyl-1H-indole (8b): See Table 1, En-
try 6. Pale yellow crystalline powder; m.p. 71–72 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.54 (t, J = 7.3 Hz, 3 H, CH3), 4.26 (q, J
= 7.3 Hz, 2 H, NCH2), 7.27–7.33 (m, 2 H, 5Ј-H and 6Ј-H), 7.40
(dm, J = 8.0 Hz, 1 H, 7Ј-H), 8.43 (s, 1 H, 2Ј-H), 8.60 (dm, J =
8.0 Hz, 1 H, 4Ј-H), 8.78 (s, 1 H, 6-H), 9.11 (s, 1 H, 2-H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 15.22 (CH3), 41.69 (NCH2), 109.62
(C-7Ј), 111.60 (C-3Ј), 116.45 (C-5), 121.73 (C-5Ј), 122.99 (C-6Ј),
123.14 (C-4Ј), 127.33 (C-3Јa), 132.32 (C-2Ј), 136.01 (C-7Јa), 156.31
(C-2), 159.34 (C-6), 159.53 (C-4) ppm. C14H12BrN3 (302.18): calcd.
C 55.65, H 4.00, N 13.91; found C 55.39, H 4.00, N 13.74. GC: tR
= 26.11 min. MS: m/z (%) = 301 (100) [M]+ for 79Br, 303 (100)
[M]+ for 81Br.
5-Bromo-4-(1H-pyrrol-2-yl)pyrimidine (4a): See Table 1, Entry 1.
Pale yellow powder; m.p. 146–147 °C. 1H NMR (400 MHz,
CDCl3): δ = 6.41 (dt, J = 3.9, 2.7 Hz, 1 H, 4Ј-H), 7.08 (td, J = 2.7,
1.3 Hz, 1 H, 5Ј-H), 7.65 (ddd, J = 3.9, 2.7, 1.3 Hz, 1 H, 3Ј-H), 8.73
(s, 1 H, 6-H), 8.90 (s, 1 H, 2-H), 10.00 (br. s, 1 H, NH) ppm. 13C
NMR (126 MHz, CDCl3): δ = 112.45 (C-4Ј), 114.75 (C-5), 117.30
(C-3Ј), 123.70 (C-5Ј), 128.41 (C-2Ј), 154.28 (C-4), 156.78 (C-2),
160.97 (C-6) ppm. C8H6BrN3 (224.06): calcd. C 42.89, H 2.70, N
18.75; found C 42.75, H 2.55, N 18.84. GC: tR = 18.81 min. MS:
m/z (%) = 223 (100) [M]+ for 79Br, 225 (100) [M]+ for 81Br.
General Procedure for the Syntheses of 4-(Hetero)aryl-Substituted
Pyrimidines 5a, 5b, 9a, and 9b: Compound 3a, 3b, 7a, or 7b
(0.5 mmol) was dissolved in piperidine (5 mL). The resulting solu-
tion was stirred at room temperature for 24 h. The solvent was
removed by distillation under reduced pressure, and the residue was
purified by flash column chromatography (hexane/ethyl acetate,
H
1:2) to afford the desired SN cine product 5a, 5b, 9a, or 9b.
5-Bromo-4-(1-metyl-1H-pyrrol-2-yl)pyrimidine (4b): See Table 1,
Entry 2. White crystalline powder; m.p. 41–43 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.92 (s, 3 H, NCH3), 6.25 (dd, J = 4.0,
2.6 Hz, 1 H, 4Ј-H), 6.85 (dd, J = 2.6, 1.7 Hz, 1 H, 5Ј-H), 7.23 (dd,
J = 4.0, 1.7 Hz, 1 H, 3Ј-H), 8.82 (s, 1 H, 6-H), 9.01 (s, 1 H, 2-
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 38.03 (NCH3), 108.74
(C-4Ј), 118.15 (C-5), 118.34 (C-3Ј), 128.25 (C-2Ј), 129.67 (C-5Ј),
156.64 (C-2), 157.18 (C-4), 160.82 (C-6) ppm. C9H8BrN3 (238.09):
calcd. C 45.40, H 3.39, N 17.65; found C 45.20, H 3.31, N 17.68.
4-(1H-Pyrrol-2-yl)pyrimidine (5a): See Table 1, Entry 3. Pale beige
crystalline powder; m.p. 116–118 °C. 1H NMR (400 MHz, CDCl3):
δ = 6.35 (dt, J = 3.7, 2.7 Hz, 1 H, 4Ј-H), 6.90 (ddd, J = 3.7, 2.5,
1.3 Hz, 1 H, 3Ј-H), 7.01 (td, J = 2.7, 1.3 Hz, 1 H, 5Ј-H), 7.42 (dd,
J = 5.5, 1.4 Hz, 1 H, 5-H), 8.56 (d, J = 5.5 Hz, 1 H, 6-H), 9.01 (d,
J = 1.4 Hz, 1 H, 2-H), 9.76 (br. s, 1 H, NH) ppm. 13C NMR
Eur. J. Org. Chem. 2012, 6612–6621
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6617

E. V. Verbitskiy et al.
FULL PAPER
(126 MHz, CDCl3): δ = 111.06 (C-3Ј), 111.27 (C-4Ј), 114.44 (C-5),
122.22 (C-5Ј), 129.04 (C-2Ј), 156.18 (C-4), 156.44 (C-6), 158.63 (C-
2) ppm. C8H7N3 (145.17): calcd. C 66.19, H 4.86, N 28.95; found
C 65.96, H 4.79, N 28.76. GC: tR = 15.82 min. MS: m/z (%) = 145
(100) [M]+.
General Procedure for the Microwave-Assisted Suzuki Cross-Cou-
pling Reactions: A solution of K2CO3 (346 mg, 2.5 mmol) in H2O
(4 mL) was added to a mixture of bromo-substituted pyrimidine 1,
4b, or 8b (1.0 mmol), the corresponding arylboronic acid 10, 13, or
14 (1.2 mmol), and Pd(PPh3)4 (58 mg, 5 mol-%) in THF (3 mL).
The resulting mixture was deaerated by bubbling argon through it
and then irradiated in a microwave apparatus at 155 °C (250 W)
for 10 min. That solvent was then removed under reduced pressure,
and the residue was purified by flash column chromatography (hex-
ane/ethyl acetate, 1:2) to afford the desired cross-coupling product
11b, 12b, 15, 16, or 17.
4-(1-Methyl-1H-pyrrol-2-yl)pyrimidine (5b): See Table 1, Entry 4.
1
Pale yellow powder; m.p. 74–76 °C. H NMR (400 MHz, CDCl3):
δ = 4.09 (s, 3 H, NCH3), 6.21 (dd, J = 3.9, 2.5 Hz, 1 H, 4Ј-H), 6.81
(dd, J = 2.5, 1.8 Hz, 1 H, 5Ј-H), 6.84 (dd, J = 3.9, 1.8 Hz, 1 H, 3Ј-
H), 7.45 (dd, J = 5.6, 1.3 Hz, 1 H, 5-H), 8.54 (d, J = 5.6 Hz, 1 H,
6-H), 9.06 (d, J = 1.3 Hz, 1 H, 2-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 37.97 (NCH3), 108.55 (C-4Ј), 114.16 (C-3Ј), 116.67 (C-
5), 129.12 (C-2Ј), 129.37 (C-5Ј), 156.02 (C-6), 158.17 (C-2), 158.46
(C-4) ppm. C9H9N3 (159.19): calcd. C 67.91, H 5.70, N 26.40;
found C 67.86, H 5.60, N 26.46. GC: tR = 16.42 min. MS: m/z (%)
= 159 (100) [M]+.
4-(1-Methyl-1H-pyrrol-2-yl)-5-(3-nitrophenyl)pyrimidine (11b): See
Table 2, Entry 1. Yellow powder; m.p. 105–107 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 3.88 (s, 3 H, NCH3), 5.64 (dd, J =
3.9, 1.7 Hz, 1 H, 3Ј-H), 5.90 (dd, J = 3.9, 2.6 Hz, 1 H, 4Ј-H), 6.95
(dd, J = 2.6, 1.7 Hz, 1 H, 5Ј-H), 7.70 (td, J = 7.8, 0.8 Hz, 1 H, 5ЈЈ-
H), 7.82 (dt, J = 7.6, 1.4 Hz, 1 H, 6ЈЈ-H), 8.24 (dd, J = 2.4, 1.6 Hz,
1 H, 2ЈЈ-H), 8.26 (ddd, J = 7.9, 2.4, 1.2 Hz, 1 H, 4ЈЈ-H), 8.73 (s, 1 H,
6-H), 9.18 (s, 1 H, 2-H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ
= 36.30 (NCH3), 107.75 (C-4Ј), 116.05 (C-3Ј), 122.88 (C-4ЈЈ),
123.80 (C-2ЈЈ), 127.58 (C-2Ј), 127.97 (C-5Ј), 129.91 (C-5), 130.14
(C-5ЈЈ), 136.04 (C-6ЈЈ), 138.62 (C-1ЈЈ), 147.98 (C-3ЈЈ), 155.82 (C-
4), 157.17 (C-2), 157.55 (C-6) ppm. C15H12N4O2 (280.29): calcd. C
3-(Pyrimidin-4-yl)-1H-indole (9a):[10] See Table 1, Entry 7. Beige
powder; m.p. 166–168 °C (decomp); ref.[10a] m.p. 165 °C. 1H NMR
(400 MHz, CD3CN): δ = 7.29–7.34 (m, 2 H, 5Ј-H and 6Ј-H), 7.47
(m, 1 H, 7Ј-H), 7.65 (dd, J = 5.4, 1.4 Hz, 1 H, 5-H), 8.02 (d, J =
2.9 Hz, 1 H, 2Ј-H), 8.41 (m, 1 H, 4Ј-H), 8.64 (d, J = 5.4 Hz, 1 H,
6-H), 8.69 (br. s, 1 H, NH), 9.19 (d, J = 1.4 Hz, 1 H, 2-H) ppm.
C12H9N3 (195.23): calcd. C 73.83, H 4.65, N 21.52; found C 73.75,
H 4.53, N 21.72. GC: tR = 24.63 min. MS: m/z (%) = 195 (100)
[M]+.
64.28, H 4.32, N 19.99; found C 64.21, H 4.25, N 19.96. GC: tR
=
26.07 min. MS: m/z (%) = 280 (100) [M]+.
1-Ethyl-3-[5-(3-nitrophenyl)pyrimidin-4-yl]-1H-indole (12b): See
1
Table 2, Entry 2. Dark yellow powder; m.p. 150–152 °C. H NMR
(500 MHz, CDCl3): δ = 1.39 (t, J = 7.3 Hz, 3 H, CH3), 4.01 (q, J
= 7.3 Hz, 2 H, NCH2), 6.72 (s, 1 H, 2Ј-H), 7.20 (ddd, J = 8.0, 6.9,
1.0 Hz, 1 H, 5Ј-H), 7.26 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H, 6Ј-H), 7.31
(dm, J = 8.1 Hz, 1 H, 7Ј-H), 7.58 (t, J = 7.9 Hz, 1 H, 5ЈЈ-H), 7.72
(dt, J = 7.7, 1.4 Hz, 1 H, 6ЈЈ-H), 8.24 (dm, J = 8.0 Hz, 1 H, 4Ј-H),
8.27 (ddd, J = 8.2, 2.2, 1.1 Hz, 1 H, 4ЈЈ-H), 8.30 (t, J = 1.9 Hz, 1
H, 2Ј-H), 8.57 (s, 1 H, 6-H), 9.25 (s, 1 H, 2-H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 15.14 (CH3), 41.29 (NCH2), 109.61 (C-7Ј),
1-Ethyl-3-(pyrimidin-4-yl)-1H-indole (9b): See Table 1, Entry 8. Red
powder; m.p. 92–94 °C. 1H NMR (400 MHz, CD3CN): δ = 1.40 (t,
J = 7.2 Hz, 3 H, CH3), 4.20 (q, J = 7.2 Hz, 2 H, NCH2), 7.16–7.24
(m, 2 H, 5Ј-H and 6Ј-H), 7.44 (dm, J = 8.0 Hz, 1 H, 7Ј-H), 7.61
(dd, J = 5.5, 1.4 Hz, 1 H, 5-H), 8.05 (s, 1 H, 2Ј-H), 8.41 (dm, J =
8.0 Hz, 1 H, 4Ј-H), 8.49 (d, J = 5.5 Hz, 1 H, 6-H), 8.98 (d, J =
1.4 Hz, 1 H, 2-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 15.20
(CH3), 41.53 (NCH2), 110.04 (C-7Ј), 113.41 (C-3Ј), 116.12 (C-5), 111.92 (C-3Ј), 121.55 (C-5Ј), 122.39 (C-4Ј), 122.94 (C-6Ј), 123.05
121.44 and 121.54 (C-4Ј and C-5Ј), 122.67 (C-6Ј), 125.96 (C-3Јa), (C-4ЈЈ), 124.10 (C-2ЈЈ), 126.61 (C-3Јa), 129.23 (C-5), 129.97 (C-5ЈЈ),
129.85 (C-2Ј), 137.08 (C-7Јa), 156.03 (C-6), 158.77 (C-2), 161.54
131.09 (C-2Ј), 135.52 (C-6ЈЈ), 136.16 (C-7Јa), 139.57 (C-1ЈЈ), 148.77
(C-4) ppm. C14H13N3 (223.28): calcd. C 75.31, H 5.87, N 18.82; (C-3ЈЈ), 156.81 (C-6), 158.17 (C-2), 159.71 (C-4) ppm. C20H16N4O2
found C 75.52, H 5.88, N 18.60. GC: tR = 24.61 min. MS: m/z (%)
(344.38): calcd. C 69.76, H 4.68, N 16.27; found C 69.60, H 4.46,
= 223 (100) [M]+.
N 16.23. GC: tR = 32.42 min. MS: m/z (%) = 344 (100) [M]+.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6612–6621

H
Consecutive SN and Suzuki–Miyaura Cross-Coupling Reactions
removed under reduced pressure as above, and then the residue was
dissolved in THF (3 mL). A solution of KOH (112 mg, 2.0 mmol,
4 equiv.) and K3Fe(CN)6 (329 mg, 1.0 mmol, 2 equiv.) in water
(3 mL) was added, and the resulting mixture was heated at reflux
for 2 h. After cooling to room temperature, the solvent was evapo-
rated under reduced pressure, and the residue was purified by flash
column chromatography (hexane/ethyl acetate, 1:2) to afford the
H
desired SN products 20b or 21b.
5-(3-Nitrophenyl)pyrimidine (15): Pale yellow powder (165 mg,
82%); m.p. 158–160 °C. 1H NMR (400 MHz, CD3CN): δ = 7.78
(t, J = 8.0 Hz, 1 H, 5Ј-H), 8.09 (ddd, J = 7.7, 1.9, 1.0 Hz, 1 H, 6Ј-
H), 8.31 (ddd, J = 8.2, 2.3, 1.0 Hz, 1 H, 4Ј-H), 8.54 (t, J = 2.0 Hz,
1 H, 2Ј-H), 9.08 (s, 2 H, 4-H and 6-H), 9.21 (s, 1 H, 2-H) ppm. 13
C
NMR (126 MHz, CD3CN): δ = 123.35 (C-2Ј), 124.97 (C-4Ј), 132.05
(C-5Ј), 133.50 (C-5), 134.84 (C-6Ј), 137.69 (C-1Ј), 150.46 (C-3Ј),
156.68 (C-4 and C-6), 159.62 (C-2) ppm. C10H7N3O2 (201.19):
calcd. C 59.70, H 3.51, N 20.89; found C 59.74, H 3.60, N 20.64.
GC: tR = 21.01 min. MS: m/z (%) = 201 (100) [M]+.
5-(3-Nitrophenyl)-4-(1H-pyrrol-2-yl)pyrimidine (11a): See Table 3,
Entry 1. Yellow powder; m.p. 153–155 °C. 1H NMR (500 MHz,
CDCl3): δ = 5.56 (ddd, J = 3.8, 2.5, 1.3 Hz, 1 H, 3Ј-H), 6.08 (dt, J
= 3.8, 2.6 Hz, 1 H, 4Ј-H), 6.96 (td, J = 2.6, 1.3 Hz, 1 H, 5Ј-H), 7.71
(t, J = 7.8 Hz, 1 H, 5ЈЈ-H), 7.75 (dt, J = 7.6, 1.5 Hz, 1 H, 6ЈЈ-H),
8.28 (t, J = 1.9 Hz, 1 H, 2ЈЈ-H), 8.37 (ddd, J = 8.0, 2.2, 1.5 Hz, 1
H, 4ЈЈ-H), 8.42 (s, 1 H, 6-H), 9.06 (s, 1 H, 2-H), 9.99 (br. s, 1 H,
NH) ppm. 13C NMR (126 MHz, CDCl3): δ = 111.45 (C-4Ј), 114.75
(C-3Ј), 122.20 (C-5Ј), 123.67 (C-4ЈЈ), 124.38 (C-2ЈЈ), 127.38 (C-5),
127.63 (C-2Ј), 130.20 (C-5ЈЈ), 135.56 (C-6ЈЈ), 138.43 (C-1ЈЈ), 148.75
(C-3ЈЈ), 153.54 (C-4), 157.23 (C-6), 157.83 (C-2) ppm. C14H10N4O2
(266.26): calcd. C 63.15, H 3.79, N 21.04; found C 63.06, H 3.76,
N 20.85. GC: tR = 26.44 min. MS: m/z (%) = 266 (100) [M]+.
5-(Thiophen-2-yl)pyrimidine (16):[12] Pale yellow powder (105 mg,
65%); m.p. 77–78 °C. H NMR (400 MHz, CDCl3): δ = 7.18 (dd,
J = 5.0, 3.6 Hz, 1 H, 4Ј-H), 7.44 (dd, J = 3.6, 1.1 Hz, 1 H, 3Ј-H),
7.47 (dd, J = 5.0, 1.1 Hz, 1 H, 5Ј-H), 8.98 (s, 2 H, 4-H and 6-H),
9.13 (s, 1 H, 2-H) ppm. C8H6N2S (162.21): calcd. C 59.24, H 3.73,
N 17.27, S 19.77; found C 59.18, H 3.63, N 17.55, S 19.64. GC: tR
= 16.04 min. MS: m/z (%) = 162 (100) [M]+.
1
5-(Thiophen-3-yl)pyrimidine (17):[15] Pale beige powder (135 mg,
83%). M.p. 102–103 °C; ref.[15] m.p. 97–98 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.41 (dd, J = 5.0, 1.4 Hz, 1 H, 4Ј-H), 7.51 (dd, J =
5.0, 3.0 Hz, 1 H, 5Ј-H), 7.61 (dd, J = 3.0, 1.4 Hz 1 H, 2Ј-H), 8.96
(s, 2 H, 4, 6-H), 9.15 (s, 1 H, 2-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 122.51 (C-2Ј), 125.34 (C-4Ј), 127.77 (C-5Ј), 129.49 (C-
5), 135.06 (C-3Ј), 154.13 (C-4 and C-6), 157.15 (C-2) ppm.
C8H6N2S (162.21): calcd. C 59.24, H 3.73, N 17.27, S 19.77; found
C 59.28, H 3.59, N 17.47, S 19.66. GC: tR = 16.40 min. MS: m/z
(%) = 162 (100) [M]+.
4-(1H-Pyrrol-2-yl)-5-(thiophen-2-yl)pyrimidine (18a): See Table 3,
Entry 3. Yellow powder; m.p. 139–141 °C. 1H NMR (500 MHz,
CDCl3): δ = 5.91 (ddd, J = 3.8, 2.5, 1.3 Hz, 1 H, 3Ј-H), 6.13 (dt, J
= 3.8, 2.6 Hz, 1 H, 4Ј-H), 6.94 (td, J = 2.6, 1.3 Hz, 1 H, 5Ј-H), 7.14
(dd, J = 3.5, 1.2 Hz, 1 H, 3ЈЈ-H), 7.19 (dd, J = 5.1, 3.5 Hz, 1 H,
4ЈЈ-H), 7.51 (dd, J = 5.1, 1.2 Hz, 1 H, 5ЈЈ-H), 8.51 (s, 1 H, 6-H),
8.99 (s, 1 H, 2-H), 9.92 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 111.29 (C-4Ј), 114.69 (C-3Ј), 121.89 (C-5Ј), 122.72 (C-
5), 127.26 (C-5ЈЈ), 127.75 (C-4ЈЈ), 127.84 (C-2Ј), 128.09 (C-3ЈЈ),
136.64 (C-2ЈЈ), 154.91 (C-4), 157.61 (C-2), 158.55 (C-6) ppm.
C12H9N3S (227.29): calcd. C 63.41, H 3.99, N 18.49; found C 63.36,
H 3.76, N 18.55. GC: tR = 22.60 min. MS: m/z (%) = 227 (100)
[M]+.
H
General Procedure for the Syntheses of SN Products Ϫ 4,5-Di-
(hetero)aryl-Substituted Pyrimidines 11a, 11b, 12a, 12b, 18a, 18b–
21a, and 21b: To a stirred mixture of 5-(hetero)aryl-pyrimidine 15,
16, or 17 (0.5 mmol) and compound 2a, 2b, 6a, or 6b (1.0 mmol)
in MeOH (3 mL) was added BF3·Et2O (1.1 mmol). The reaction
mixture was stirred at room temperature for 24 h, and the solvent
was evaporated. A solution of KOH (112 mg, 2.0 mmol, 4 equiv.)
and K3Fe(CN)6 (329 mg, 1.0 mmol, 2 equiv.) in water (5 mL) was
added to residue. The resulting mixture was stirred for the appro-
priate time (see Table 3) at room temperature. The precipitate or
semisolid was removed by filtration, washed with H2O, and then air
dried. The residue was purified by flash column chromatography
(hexane/ethyl acetate, 1:2) to afford the desired SNH products. How-
4-(1-Methyl-1H-pyrrol-2-yl)-(5-thiophen-2-yl)pyrimidine (18b): See
Table 3, Entry 4. Yellow oil. 1H NMR (500 MHz, CDCl3): δ = 3.58
H
ever, in the case of SN products 20b and 21b, the solvent was
Eur. J. Org. Chem. 2012, 6612–6621
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6619

E. V. Verbitskiy et al.
FULL PAPER
(s, 3 H, NCH3), 6.19 (dd, J = 2.9, 1.8 Hz, 1 H, 3Ј-H), 6.46 (t, J =
2.6 Hz, 1 H, 4Ј-H), 6.87 (t, J = 2.0 Hz, 1 H, 5Ј-H), 7.09 (dd, J =
3.5, 1.2 Hz, 1 H, 3ЈЈ-H), 7.14 (dd, J = 5.1, 3.5 Hz, 1 H, 4ЈЈ-H), 7.46
(dd, J = 5.1, 1.2 Hz, 1 H, 5ЈЈ-H), 8.50 (s, 1 H, 6-H), 9.02 (s, 1 H,
1.34 (t, J = 7.3 Hz, 3 H, CH3), 4.04 (q, J = 7.3 Hz, 2 H, NCH2),
6.88 (s, 1 H, 2Ј-H), 7.10–7.13 (m, 2 H, 3ЈЈ-H and 4ЈЈ-H), 7.22 (ddd,
J = 8.0, 6.8, 1.3 Hz, 1 H, 5Ј-H), 7.26 (ddd, J = 8.1, 6.8, 1.1 Hz, 1
H, 6Ј-H), 7.32 (dm, J = 8.1 Hz, 1 H, 7Ј-H), 7.43 (dd, J = 4.7,
2-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 36.44 (NCH3), 2.0 Hz, 1 H, 5ЈЈ-H), 8.40 (dm, J = 8.0 Hz, 1 H, 4Ј-H), 8.59 (s, 1 H,
109.85 (C-3Ј), 121.64 (C-2Ј), 122.55 (C-4Ј), 123.82 (C-5), 125.49 (C- 6-H), 9.17 (s, 1 H, 2-H) ppm. 13C NMR (126 MHz, CDCl3): δ =
5Ј), 126.86 (C-5ЈЈ), 127.53 (C-4ЈЈ), 127.83 (C-3ЈЈ), 137.90 (C-2ЈЈ),
157.84 (C-2), 158.21 (C-6), 159.87 (C-4) ppm. C13H11N3S (241.32):
calcd. C 64.71, H 4.59, N 17.41; found C 64.66, H 4.76, N 17.47.
GC: tR = 22.53 min. MS: m/z (%) = 241 (100) [M]+.
15.04 (CH3), 41.22 (NCH2), 109.41 (C-7Ј), 111.93 (C-3Ј), 121.41
(C-5Ј), 122.54 (C-6Ј), 122.66 (C-4Ј), 124.77 (C-5), 127.04 (C-5ЈЈ),
127.09 (C-3Јa), 127.64 and 127.70 (C-3ЈЈ and C-4ЈЈ), 131.32 (C-2Ј),
136.04 (C-7Јa), 138.44 (C-2ЈЈ), 157.45 (C-6), 157.74 (C-2), 160.78
(C-4) ppm. C18H15N3S (305.40): calcd. C 70.79, H 4.95, N 13.76;
found C 70.66, H 5.00, N 13.69. GC: tR = 27.90 min. MS: m/z (%)
= 305 (100) [M]+.
4-(1H-Pyrrol-2-yl)-5-(thiophen-3-yl)pyrimidine (19a): See Table 3,
Entry 5. Beige powder; m.p. 140–141 °C. 1H NMR (500 MHz,
CDCl3): δ = 5.87 (ddd, J = 3.8, 2.5, 1.3 Hz, 1 H, 3Ј-H), 6.13 (dt, J
= 3.8, 2.6 Hz, 1 H, 4Ј-H), 6.94 (td, J = 2.6, 1.3 Hz, 1 H, 5Ј-H), 7.13
(dd, J = 5.0, 1.3 Hz, 1 H, 4ЈЈ-H), 7.35 (dd, J = 3.0, 1.3 Hz, 1 H,
2ЈЈ-H), 7.49 (dd, J = 5.0, 3.0 Hz, 1 H, 5ЈЈ-H), 8.45 (s, 1 H, 6-H),
8.99 (s, 1 H, 2-H), 9.93 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 111.14 (C-4Ј), 114.37 (C-3Ј), 121.70 (C-5Ј), 124.33 (C-
2ЈЈ), 125.03 (C-5), 126.65 (C-5ЈЈ), 128.19 (C-2Ј), 128.44 (C-4ЈЈ),
136.53 (C-3ЈЈ), 154.10 (C-4), 157.12 (C-2), 157.65 (C-6) ppm.
C12H9N3S (227.29): calcd. C 63.41, H 3.99, N 18.49; found C 63.56,
H 4.06, N 18.66. GC: tR = 22.83 min. MS: m/z (%) = 227 (100)
[M]+.
1-Ethyl-3-[5-(thiophen-3-yl)pyrimidin-4-yl]-1H-indole (21b): See
Table 3, Entry 12. Yellow oil. 1H NMR (500 MHz, CDCl3): δ =
1.34 (t, J = 7.3 Hz, 3 H, CH3), 4.03 (q, J = 7.3 Hz, 2 H, NCH2),
6.78 (s, 1 H, 2Ј-H), 7.01 (dd, J = 4.9, 1.4 Hz, 1 H, 4ЈЈ-H), 7.22
(ddd, J = 8.0, 6.9, 1.2 Hz, 1 H, 5Ј-H), 7.26 (ddd, J = 8.1, 6.9,
1.1 Hz, 1 H, 6Ј-H), 7.32 (dm, J = 8.1 Hz, 1 H, 7Ј-H), 7.36 (dd, J
= 3.0, 1.4 Hz, 1 H, 2ЈЈ-H), 7.38 (dd, J = 4.9, 3.0 Hz, 1 H, 5ЈЈ-H),
8.41 (dm, J = 8.0 Hz, 1 H, 4Ј-H), 8.55 (s, 1 H, 6-H), 9.17 (s, 1 H,
2-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 15.02 (CH3), 41.18
(NCH2), 109.38 (C-7Ј), 112.31 (C-3Ј), 121.37 (C-5Ј), 122.56 (C-6Ј),
122.68 (C-4Ј), 123.92 (C-2ЈЈ), 126.51 (C-5ЈЈ), 126.79 (C-5), 127.01
(C-3Јa), 128.26 (C-4ЈЈ), 131.19 (C-2Ј), 136.09 (C-7Јa), 138.02 (C-
3ЈЈ), 156.70 (C-6), 157.43 (C-2), 160.13 (C-4) ppm. C18H15N3S
(305.40): calcd. C 70.79, H 4.95, N 13.76; found C 70.87, H 4.77,
N 13.90. GC: tR = 29.34 min. MS: m/z (%) = 305 (100) [M]+.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of the new com-
pounds. Detailed information in Table S4 concerning crystal struc-
tures of compounds 3b, 4a, 8a, 8b, and 18a provided by X-ray
analysis.
4-(1-Methyl-1H-pyrrol-2-yl)-5-(thiophen-3-yl)pyrimidine (19b): See
Table 3, Entry 6. Pale yellow oil. 1H NMR (500 MHz, CDCl3): δ
= 3.76 (s, 3 H, NCH3), 6.02–6.05 (m, 2 H, 3Ј-H and 4Ј-H), 6.71 (t,
J = 2.1 Hz, 1 H, 5Ј-H), 6.91 (dd, J = 5.0, 1.3 Hz, 1 H, 4ЈЈ-H), 7.26
(dd, J = 3.0, 1.3 Hz, 1 H, 2ЈЈ-H), 7.33 (dd, J = 5.0, 3.0 Hz, 1 H, 5ЈЈ-
H), 8.63 (s, 1 H, 6-H), 9.08 (s, 1 H, 2-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 36.50 (NCH3), 108.11 (C-4Ј), 115.56 (C-3Ј), 123.64
(C-2ЈЈ), 126.22 (C-5ЈЈ), 127.24 (C-5Ј), 127.68 (C-5), 127.73 (C-4ЈЈ),
128.74 (C-2Ј), 137.08 (C-3ЈЈ), 156.26 (C-4), 156.67 (C-2), 157.19 (C-
6) ppm. C13H11N3S (241.32): calcd. C 64.71, H 4.59, N 17.41;
found C 64.57, H 4.67, N 17.35. GC: tR = 22.82 min. MS: m/z (%)
= 241 (100) [M]+.
Acknowledgments
This work was supported by the Ural Branch of the Russian Acad-
emy of Sciences (grants numbers 12-P-3-1014, 12-P-3-1030, 12-T-
3-1025, and 12-T-3-1031), the State Program for Supporting of
Leading Scientific Schools of the Russian Federation (grant
number NSh 5505.2012.3), and the Russian Foundation for Basic
Research (grant numbers 10-03-96078-r_ural_a and 12-03-31574).
[1] A. de Meijere, F. Diederich (Eds.), Metal-Catalyzed Cross-Cou-
pling Reactions, 2nd ed., Wiley-VCH, Weinheim, Germany,
2004.
[2] J. Tsuji, Palladium Reagents and Catalysts, 2nd ed., Wiley,
Chichester, UK, 2004.
[3] J. Hassan, M. Sévignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359.
[4] a) N. Miaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) N.
Miaura, Top. Curr. Chem. 2002, 219, 11; c) G. Bringmann, C.
1-Ethyl-3-[5-(thiophen-2-yl)pyrimidin-4-yl]-1H-indole (20b): See
Table 3, Entry 10. Yellow oil. 1H NMR (500 MHz, CDCl3): δ =
6620
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6612–6621

H
Consecutive SN and Suzuki–Miyaura Cross-Coupling Reactions
Gunther, M. Ochse, O. Schupp, S. Tasler, in: Progress in the
Chemistry of the Organic Natural Products (Eds.: W. Her, H.
Falk, G. W. Kirby, R. E. Moore), Springer, New York, 2001,
vol. 82, pp. 1–293; d) D. G. Hall, Boronic Acids: Preparation
and Application in Organic Synthesis and Medicine, Wiley-
VCH, Weinheim, Germany, 2005; e) B. L. Hayes, Microwave
Synthesis: Chemistry at the Speed of Light, CEM Publishing,
Matthews, NC, 2002.
[9]
a) E. W. Wienhoefer, T. Kauffmann, Tetrahedron Lett. 1974,
27, 2347; b) T. Kauffmann, J. Konig, D. Koerber, H. Lexy,
H. J. Streitberger, A. Vahrenhorst, A. Woltermann, Tetrahedron
Lett. 1977, 4, 389.
a) H. Biere, H. Wachtel, D. Palenschat, R. Horowski, G. Pasch-
elke, W. Kehr, DE Patent DE2406799A1, 1974) [Chem. Abstr.
1976, 84, 44114d]; b) T. V. Stupnikova, T. V. Nuzhnaya, N. A.
Klyuev, A. Yu. Chervinskii, Chem. Heterocycl. Compd. 1982,
18, 164.
a) W. Girke, Tetrahedron Lett. 1976, 39, 3537; b) W. P. K. Girke,
Chem. Ber. 1979, 112, 1; c) W. P. K. Girke, Chem. Ber. 1979,
112, 1348.
E. V. Verbitskiy, E. M. Cheprakova, P. A. Slepukhin, M. I. Ko-
dess, M. A. Ezhikova, M. G. Pervova, G. L. Rusinov, O. N.
Chupakhin, V. N. Charushin, Tetrahedron 2012, 68, 5445.
[10]
[5] For selected reviews on nucleophilic aromatic substitution of
hydrogen, see: a) O. N. Chupakhin, V. N. Charushin, H. C.
van der Plas, Nucleophilic Aromatic Substitution of Hydrogen,
Academic Press, New York, 1994; b) V. N. Charushin, O. N.
Chupakhin, Pure Appl. Chem. 2004, 76, 1621; c) V. N. Cha-
rushin, O. N. Chupakhin, Mendeleev Commun. 2007, 17, 249;
d) M. Makosza, K. Wojciechowski, Chem. Rev. 2004, 104,
2631; e) M. Makosza, Chem. Soc. Rev. 2010, 39, 2855.
[6] D. Brown in Comprehensive Heterocyclic Chemistry I (Eds.:
A. R. Katritzky, C. W. Rees), Pergamon Press, Oxford, 1996,
vol. 3, ch. 2.13.
[7] A. T. Soldatenkov, N. M. Kolyadina, I. V. Sheldrik, Osnovy or-
ganicheskoi khimii lekarstvennykh sredsv (Principles of the Or-
ganic Chemistry of Drugs), Khimiya, Moscow, 2001 [in Rus-
sian].
[8] R. J. Sundberg, in: Comprehensive Heterocyclic Chemistry I
(Eds.: A. R. Katritzky, C. W. Rees), Pergamon Press, Oxford,
UK, 1996, vol. 3, chapter 3.06.
[11]
[12]
[13] F. L. Tietze, T. Eicher, Reaktionen und Synthesen im organisch-
chemischen Praktikum und Forschunglaboratorium, Thieme,
Stuttgart, Germany, 1991.
[14] N. N. Suvorov, Yu. I. Smushkevich, V. S. Velezheva, V. S. Rozh-
kov, S. V. Simakov, Chem. Heterocycl. Compd. 1976, 12, 167.
[15] G. A. Molander, B. Biolatto, J. Org. Chem. 2003, 68, 4302.
Received: August 2, 2012
Published Online: October 8, 2012
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6621