Synthesis of 4,6-disubstituted 2-(4-morpholinyl)pyrimidines by cross-coupling reactions using triorganoindium compounds

Article abstract of DOI:10.1039/c2ob26398j

4,6-Disubstituted-2-(4-morpholinyl)pyrimidines, an important class of bioactive compounds, have been synthesized from 4,6-dichloro-2-(4-morpholinyl) pyrimidine by selective and sequential palladium-catalyzed cross-coupling reactions using triorganoindium reagents. This methodology, being efficient and versatile, allowed the synthesis of a variety of non-symmetrical pyrimidines functionalized at C-4 and C-6 positions.

Full text of DOI:10.1039/c2ob26398j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 9045
www.rsc.org/obc
PAPER
Synthesis of 4,6-disubstituted 2-(4-morpholinyl)pyrimidines by cross-coupling
reactions using triorganoindium compounds†
M. Montserrat Martínez,* Cristina Pérez-Caaveiro, Miguel Peña-López, Luis A. Sarandeses and
José Pérez Sestelo*
Received 18th July 2012, Accepted 1st October 2012
DOI: 10.1039/c2ob26398j
4,6-Disubstituted-2-(4-morpholinyl)pyrimidines, an important class of bioactive compounds, have been
synthesized from 4,6-dichloro-2-(4-morpholinyl)pyrimidine by selective and sequential palladium-
catalyzed cross-coupling reactions using triorganoindium reagents. This methodology, being efficient and
versatile, allowed the synthesis of a variety of non-symmetrical pyrimidines functionalized at C-4 and C-6
positions.
PI3 kinase for treating cancer.4 An illustrative example of a syn-
thetic pharmacore based upon a pyrimidyl structural motif is
Introduction
The pyrimidine ring is an important structural motif found in
numerous natural products and bioactive compounds.1 Addition-
ally, the pyrimidine nucleus is also present as a building block in
materials science.2 As pharmacologically active compounds,
substituted pyrimidine scaffolds have become increasingly
important with antibacterial, antimicrobial, and antimycotic
activities.1 In particular, substituted pyrimidines furnished with a
saturated heterocyclic unit at the C-2 position such as 1 (Fig. 1)
display activity as antagonists of serotonin 5-HT2A receptor
ligands, and present therapeutical interest as potential psychiatric
drugs, including atypical antipsychotics, antidepressants, and
anxiolytics.3 In recent studies it was shown that the pyrimidine
NVP-BKM120 (2) is a potent and selective inhibitor of class I
rosuvastatin (3), which is a commercial statin used to reduce
hyperlipidemia (Fig. 1).5
Traditionally, the synthesis of functionalized pyrimidines has
been achieved by construction of the pyrimidine ring through
condensation reactions of 1,3-dicarbonyl compounds with ami-
dines or amidinium salts,1 or based on the functionalization of
the pyrimidine ring, using a direct metallation strategy or
through nucleophilic aromatic substitution reactions.1,6 However,
in recent years the cross-coupling reactions have been shown as
a powerful methodology for the regioselective functionalization
of halopyrimidines.7 In this reaction, the best selectivity is
usually achieved using chloropyrimidines, and the general order
of reactivity is C4(6) > C2 > C5.7,8
Over the last 15 years, we have shown that triorganoindium
compounds (R3In) are useful reagents in fundamental organic
transformations such as the metal-catalyzed cross-coupling reac-
tions.9 The main features of R3In are their high efficiency, trans-
ferring the three groups attached to indium, their versatility, and
high chemo- and stereoselectivity. This methodology has been
successfully applied to the synthesis of natural and non-natural
products,10 and in the selective functionalization of 3,4-dihalo-
maleimides, 2,5-dibromothiophenes and 2,5-dihalopyrimidines.11
Herein we disclose a new synthetic application of indium
organometallics with the efficient synthesis of 2,4,6-trisubstituted
pyrimidines by selective and sequential cross-coupling reactions.
Fig. 1 Representative pyrimidines with pharmacological activity.
Results and discussion
Departamento de Química Fundamental, Universidade da Coruña,
E-15071 A Coruña, Spain. E-mail: sestelo@udc.es, mmartinezc@udc.es;
Fax: +34 981 167 065; Tel: +34 981 167 000
†Electronic supplementary information (ESI) available: Copies of
1H and 13C NMR spectra for all compounds prepared. See DOI:
10.1039/c2ob26398j
Considering that pyrimidines furnished with an amino moiety
at the C-2 position have been identified as potent bioactive
compounds,3,4 we envisaged the synthesis of diverse 4,6-di-
substituted-2-aminopyrimidines by cross-coupling reactions with
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9045–9051 | 9045

View Article Online
Table 1 Selective Pd-catalyzed cross-coupling of 4,6-dichloro-2-
(4-morpholinyl)pyrimidine (4) with triorganoindium reagents
indium organometallics. As an amino substituent, we chose
the 4-morpholinyl group, present in pharmacologically active
compounds (Fig. 1).4 In this way, 4,6-dichloro-2-(4-morpholinyl)-
pyrimidine (4) was readily obtained by the reaction of N-methyl-
morpholine with 2,4,6-trichloropyrimidine.12 Reactions of differ-
ent organoindium reagents with 4 should allow the rational
functionalization and the synthesis of non-symmetrically 4,6-di-
substituted pyrimidines by selective and sequential coupling.
Our first objective was to ascertain if the coupling reaction
of the 4,6-dichloro-2-(4-morpholinyl)pyrimidine (4) with indium
organometallics occurs selectively at the equivalent C-4 or C-6
site positions. According to our experience,11 we tested the
reaction of pyrimidine 4 with triphenylindium (40 mol%) using
Pd(dppf)Cl2 (4 mol%) as catalyst in THF at 80 °C. In this
experiment, we found a mixture of the monocoupling product 5a
(41% yield) and the dicoupling product (20% yield). Other
Pd(II) or Pd(0) complexes such as Pd(PhCN)2Cl2 or Pd2(dba)3/
(p-furyl)3 gave similar results, but the use of Pd(PPh3)4 (4 mol%)
provided efficiently the monocoupling product 5a in 83%
yield (Table 1, entry 1). Interestingly, just traces of the double
coupling product were observed by 1H NMR and the only
byproduct isolated was biphenyl produced by reductive dimeri-
zation of the Ph3In. In our next experiment, the growing interest
in fluorinated compounds in pharmacological sciences led us to
perform the reaction using tris(4-trifluoromethylphenyl)indium.
Under the same reaction conditions the pyrimidine 5b was
obtained in 85% yield without isolation of any dicoupling
product (Table 1, entry 2). Analogously, the reaction of
tri(naphthalen-1-yl)indium with 4 gave only the monocoupling
product 5c in 66% yield (Table 1, entry 3). The reaction with
(hetero)arylindium reagents, such as tri(thiophen-2-yl)indium
and tri(benzo[b]thiophen-2-yl)indium, also afforded the 4-susbti-
tuted-6-chloropyrimidines 5d and 5e in 70 and 74% yield,
respectively (Table 1, entries 4 and 5). In these cases, some of
the starting pyrimidine 4 and the double coupling product (less
than 10%) were recovered or isolated.
Entry
1
R1
Ph
Product
Yielda (%)
83
2
3
4-CF3–C6H4
85
66
Naphthalen-1-yl
4
5
Thiophen-2-yl
70
74
Benzo[b]thiophen-2-yl
In our research, we also focused our attention on the cyclopro-
pane moiety, which represents an important scaffold in natural
products.13 Interestingly, the palladium-catalyzed cross-coupling
reaction of 4 with the tri(cyclopropyl)indium reagent, prepared
in situ from bromocyclopropane, gave the 4-cyclopropyl pyrimi-
dine 5f in 70% yield (Table 1, entry 6).
6
7
Cyclopropyl
70
46
PhCuC
Our synthetic approach was also extended to alkynyl and
alkenylindium reagents such as tri(phenylethynyl)indium and
tri(β-styryl)indium. In these cases the monocoupling products 5g
and 5h were obtained in 46 and 42% yields respectively
(Table 1, entries 7 and 8). This moderate yield was also observed
during the selective coupling using halothiophenes.11b Neverthe-
less, the ability of R3In to transfer the three groups (aryl, hetero-
aryl, alkyl, alkenyl and alkynyl) using only 40 mol% is
remarkable.
8
(E)-PhCHvCH
42
With the 4-substituted-6-chloro-2-(4-morpholinyl)pyrimidines
5a–h in hand, we looked forward to replace the remaining
chlorine atom through a new palladium-catalyzed cross-coupling
reaction using an organoindium reagent. For this purpose
selected monocoupled products 5 were treated with a range of
(hetero)arylindium reagents as a new entry to non-symmetrically
4,6-disubstituted pyrimidines. Following the previous conditions,
the reaction of tris(4-trifluoromethylphenyl)indium (40 mol%)
with 5a gave the 4-phenyl-6-(4-trifluoromethylphenyl)pyrimi-
dine 6 in 90% yield after 16 h (Table 2, entry 1). Analogously,
when 5c was employed as an electrophile, the unsymmetrically
4,6-disubstituted pyrimidine 7 was obtained in 70% yield
(Table 2, entry 2). Attempting to explore the utility of the
methodology in the synthesis of new biologically active com-
pounds or organic materials, we studied the introduction of the
9046 | Org. Biomol. Chem., 2012, 10, 9045–9051
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Synthesis of non-symmetrical pyrimidines by second Pd-
catalyzed cross-coupling from 4-susbtituted-6-chloro-2-(4-morpholinyl)-
pyrimidines
was also incorporated into 5d giving the diheteroaryl derivative
9 in 80% yield (Table 2, entry 4). The efficiency of the cross-
coupling reaction was also demonstrated by the introduction of
the pyridin-2-yl group that is present in biologically active pyri-
midines.14 In this case the reaction of tri(pyridin-2-yl)indium
with 5d afforded the unsymmetrically disubstituted pyrimidine
10 in 66% yield (Table 2, entry 5).
We also assayed the cross-coupling of tri(thiophen-2-yl)- and
tri(2,2′-bithiophen-5-yl)indium with 5e affording compounds 11
and 12 in 73% and 74% yields (Table 2, entries 6 and 7 respecti-
vely). The reaction with other heteroaryl groups, using tri(fur-2-
yl)indium and the pyrimidine 5f as an electrophile, proved to be
satisfactory obtaining 13 in 65% yield (Table 2, entry 8).
One particular feature of the cross-coupling reactions using
indium organometallics is the suitability to perform two carbon–
carbon bonds in a one-pot reaction, either by a sequential or a
multiple cross-coupling reaction. For this reason, we assayed the
synthesis of the non-symmetrically 4,6-disubstituted pyrimidine
6 in a one-pot protocol. Under the previously developed reaction
conditions, the successive addition of Ph3In (40 mol%) and
(4-CF3C6H4)3In (40 mol%) to the 4,6-dichloropyrimidine 4 pro-
vided the desired disubstituted pyrimidine 6 in 85% overall yield
(Scheme 1).
Additionally, we also performed two-fold cross-coupling
reaction with triorganoindium reagents to obtain symmetrically
substituted pyrimidines which are of pharmacological interest
and building blocks for functional devices. The reaction of
tri(thiophen-2-yl)indium (70 mol%) with 4,6-dichloro-2-
(4-morpholinyl)pyrimidine (4), using Pd(PPh3)4 (4 mol%) as a
catalyst, gave the symmetrically 4,6-disubstituted pyrimidine 14
in 91% yield, a compound with antiviral activity.15 Analogously,
the reaction of 4 with tri(benzo[b]thiophen-2-yl)indium reagent
gave 15 in 95% yield (Scheme 1).
Yielda
(%)
Entry
1
5
R2
Product
5a 4-CF3–C6H4
90
2
5c 4-CF3–C6H4
70
3
4
5
6
5c 2,2′-Bithiophen-5-yl
5d 2,2′-Bithiophen-5-yl
5d Pyridin-2-yl
79
80
66
73
5e Thiophen-2-yl
7
8
5e 2,2′-Bithiophen-5-yl
74
65
Scheme 1 Synthesis of 4,6-disubstituted pyrimidines by Pd-catalyzed
one-pot sequential and two-fold cross-coupling reactions.
Conclusions
5f Fur-2-yl
In summary, the synthesis of new substituted pyrimidines of
pharmacological interest functionalized with aryl and heteroaryl
groups at C-4 and C-6 positions bearing an N-morpholino group
at the C-2 position has been achieved. The synthesis was com-
pleted through an efficient, versatile and selective palladium-
catalyzed cross-coupling reaction of 4,6-dichloro-2-(4-morpholi-
nyl)pyrimidine with different indium organometallics. The pro-
tocol allowed not only the incorporation of aryl and heteroaryl
organic residues but also functionalization with alkyl, alkenyl
and alkynyl groups. Overall, triorganoindium reagents are shown
to be useful alternatives to other organometallics exhibiting high
reactivity to perform selective and sequential cross-coupling
a Isolated yield.
2,2′-bithiophen-5-yl group into the pyrimidine core.2d Gratify-
ingly, the reaction of tri(2,2′-bithiophen-5-yl)indium with 5c
afforded the novel non-symmetrically substituted pyrimidine 8 in
79% yield (Table 2, entry 3). Analogously, the bithiophenyl unit
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9045–9051 | 9047

View Article Online
reactions with high atom economy. The biological activity of the
novel pyrimidines is now being evaluated and the results will be
published in due course.
residue was purified by flash chromatography (5–30% Et2O/
hexanes) to afford, after concentration and high vacuum drying,
the corresponding cross-coupling products.
4-(4-Chloro-6-phenylpyrimidin-2-yl)morpholine (5a).16 Accord-
ing to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with triphenylindium (0.2 mmol) afforded, after
purification by column chromatography (30% Et2O/hexanes),
compound 5a as a white solid (114 mg, 83%). Mp 163–164 °C
(lit.16 161–162 °C); IR (ATR) 3336, 2961, 2896, 2854, 1555,
Experimental
General methods
All reactions were carried out in flame-dried glassware, under an
argon atmosphere, using standard gastight syringes, cannula, and
septa. Tetrahydrofuran (THF) was dried by distillation from the
sodium ketyl of benzophenone. Reaction temperatures refer to
external bath temperatures. Butyllithium and phenyllithium were
titrated prior to use. All other commercially available reagents
were used as received. Organic extracts were dried over an-
hydrous MgSO4, filtered, and concentrated using a rotary evapo-
rator at aspirator pressure. Reactions were monitored by TLC
1530, 1492, 1445 cm−1
;
1H NMR (300 MHz, CDCl3)
δ 7.99–8.02 (m, 2 H), 7.46–7.49 (m, 3 H), 6.98 (s, 1 H),
3.90–3.93 (m, 4 H), 3.77–3.80 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 166.1 (C), 162.0 (C), 161.5 (C), 136.6 (C), 131.0
(CH), 128.8 (2 × CH), 127.2 (2 × CH), 105.3 (CH), 66.8
(2 × CH2), 44.4 (2 × CH2); MS (EI) m/z 277 [M+] (37Cl, 22),
275 [M+] (35Cl, 74); HRMS (EI) calcd for C14H14ON3Cl
275.0820 [M+], found 275.0816.
using precoated silica gel plates (Alugram® Xtra SIL G/UV254
,
0.20 mm thick) using UV light as a visualizing agent and
ethanolic phosphomolybdic acid as a developing agent. Flash
column chromatography was performed using 230–400 mesh
silica gel packed in glass columns. H and 13C NMR spectra were
recorded in CDCl3 at 300 MHz or 500 MHz for 1H and 75 MHz
or 125 MHz for 13C, at ambient temperature, and calibrated to
the solvent peak. DEPT data were used to assign carbon types.
Mass spectra were obtained with EI ionization at 70 eV. Melting
points are uncorrected.
4-[4-Chloro-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]mor-
pholine (5b). According to the general procedure, the reaction of
4 (117 mg, 0.5 mmol) with tris(4-trifluoromethylphenyl)indium
(0.2 mmol) afforded, after purification by column chromato-
graphy (30% Et2O/hexanes), compound 5b as a pale yellow
solid (146 mg, 85%). Mp 126–128 °C; IR (ATR) 3095, 2966,
1
2918, 2865, 1562, 1544, 1511, 1446 cm−1; H NMR (CDCl3,
300 MHz) δ 8.09 (d, J = 8.3 Hz, 2 H), 7.73 (d, J = 8.4 Hz, 2 H),
6.99 (s, 1 H), 3.78–3.93 (m, 8 H); 13C NMR (CDCl3, 75 MHz)
2
δ 164.6 (C), 162.3 (C), 161.5 (C), 139.4 (C), 132.6 (q, JCF
=
3
32.6 Hz, C), 127.5 (2 × CH), 125.6 (q, JCF = 2.7 Hz, 2 × CH),
Triorganoindium reagents
1
123.8 (q, JCF = 261.2 Hz, CF3), 105.6 (CH), 66.7 (2 × CH2),
44.4 (2 × CH2); MS (EI) m/z 345 [M+] (37Cl, 23), 343 [M+]
(35Cl, 82), 312 (100); HRMS (EI) calcd for C15H13ON3ClF3
343.0694 [M+], found: 343.0690.
Triorganoindium compounds were prepared according to pre-
viously published methods9 by treatment of the corresponding
organolithium reagents (3 equiv., ∼0.5 M in dry THF) with a
solution of InCl3 (1.1 equiv., ∼0.05 M in dry THF) at −78 °C
and warming to room temperature.
Furan, phenylacetylene and benzo[b]thiophene were lithiated
by treatment with n-BuLi (1 equiv.) at −78 °C and warming to
room temperature. 2-Bromopyridine was lithiated by treatment
with tert-BuLi (2 equiv.) at −78 °C. Other organolithium
reagents were prepared by metal–halogen exchange reactions
with n-BuLi (1 equiv.) at −78 °C in dry THF.
4-[4-Chloro-6-(naphthalen-1-yl)pyrimidin-2-yl]morpholine (5c).
According to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with tri(naphthalen-1-yl)indium (0.2 mmol) afforded,
after purification by column chromatography (30% Et2O/
hexanes), compound 5c as a white solid (108 mg, 66%). Mp
117–118 °C; IR (ATR) 2960, 2920, 2853, 1562, 1532,
1
1447 cm−1; H NMR (300 MHz, CDCl3) δ 8.24–8.27 (m, 1 H),
7.89–7.96 (m, 2 H), 7.64 (dd, J = 7.2, 1.4 Hz, 1 H), 7.51–7.56
(m, 3 H), 6.85 (s, 1 H), 3.89–3.92 (m, 4 H), 3.76–3.79 (m, 4 H);
13C NMR (75 MHz, CDCl3) δ 168.7 (C), 161.5 (C), 161.4 (C),
135.9 (C), 133.9 (C), 130.5 (C), 130.3 (CH), 128.5 (CH), 127.5
(CH), 126.7 (CH), 126.1 (CH), 125.3 (CH), 125.2 (CH), 110.1
(CH), 66.8 (2 × CH2), 44.4 (2 × CH2); MS (EI) m/z 327 [M+]
(37Cl, 51), 325 [M+] (35Cl, 96); HRMS (EI) calcd for
C18H16ON3Cl 325.0976 [M+], found: 325.0976.
General procedure for the palladium-catalyzed cross-coupling
reactions
To a solution of the electrophile (0.5 mmol) and Pd(PPh3)4
(0.02 mmol) in dry THF (2 mL) placed in an argon filled
Schlenk tube was slowly added a solution of R3In [∼0.05 M in
THF, 0.2 mmol for the site-selective coupling (Table 1),
0.2 mmol for the sequential coupling reactions (Table 2) or
0.35 mmol for the two-fold coupling reactions (Scheme 1)] and
the resulting mixture was stirred at 80 °C until the starting
material was consumed (12–20 h). The reaction mixture was
quenched by the addition of a few drops of MeOH and the
mixture was filtered through a short pad of Celite, followed by
washing the solids with Et2O. The filtrate was concentrated
in vacuo and the residue was dissolved in Et2O, washed with
brine, dried over Mg2SO4 and concentrated in vacuo. The
4-[4-Chloro-6-(thiophen-2-yl)pyrimidin-2-yl]morpholine (5d).
According to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with tri(thiophen-2-yl)indium (0.2 mmol) afforded,
after purification by column chromatography (10% Et2O/
hexanes), compound 5d as a fawn solid (99 mg, 70%). Mp
82–83 °C; IR (ATR) 3107, 2964, 2919, 2864, 1545, 1518, 1499,
1
1432 cm−1; H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 3.6 Hz,
1 H), 7.49 (d, J = 3.9 Hz, 1 H), 7.12 (dd, J = 3.9, 3.6 Hz, 1 H),
6.85 (s, 1 H), 3.85–3.89 (m, 4 H), 3.76–3.80 (m, 4 H);
9048 | Org. Biomol. Chem., 2012, 10, 9045–9051
This journal is © The Royal Society of Chemistry 2012

View Article Online
13C NMR (75 MHz, CDCl3) δ 161.6 (C), 161.2 (C), 160.6 (C),
142.3 (C), 129.9 (CH), 128.2 (CH), 127.4 (CH), 103.5 (CH),
66.8 (2 × CH2), 44.2 (2 × CH2); MS (EI) m/z 383 [M+] (37Cl,
34), 281 [M+] (35Cl, 100); HRMS (EI) calcd for C12H12ClN3OS
281.0384 [M+], found 281.0381.
(C), 129.3 (CH), 128.8 (2 × CH), 127.6 (2 × CH), 125.7 (CH),
107.4 (CH), 66.8 (2 × CH2), 44.4 (2 × CH2); MS (EI) m/z 303
[M+] (37Cl, 25), 301 [M+] (35Cl, 79); HRMS (EI) calcd for
C16H16ON3Cl 301.0976 [M+], found 301.0975.
4-[4-Phenyl-6-[4-(trifluormethyl)phenyl]pyrimidin-2-yl]morpholine
(6). According to the general procedure, the reaction of 5a
(138 mg, 0.5 mmol) with tris(4-trifluoromethylphenyl)indium
(0.2 mmol) afforded, after purification by column chromato-
graphy (30% Et2O/hexanes), compound 6 as a pale yellow solid
(160 mg, 90%).
4-[4-(Benzo[b]thiophen-2-yl)-6-chloropyrimidin-2-yl]morpholine
(5e). According to the general procedure, the reaction of 4
(117 mg, 0.5 mmol) with tri(benzo[b]thiophen-2-yl)indium
(0.2 mmol) afforded, after purification by column chromato-
graphy (10–30% Et2O/hexanes), compound 5e as a yellow solid
(123 mg, 74%). Mp 141–143 °C; IR (ATR) 3095, 2967, 2914,
Compound 6 was also prepared by sequential cross-coupling
reactions in a one-pot procedure: to a solution of 4 (117 mg,
0.5 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in dry THF
(2 mL) placed in an argon filled Schlenk tube, a solution of
triphenylindium (4.0 mL, 0.05 M in THF, 0.2 mmol) was slowly
added. After heating at 80 °C for 16 h the starting material was
consumed (TLC monitoring) and a solution of tris(4-trifluoro-
methylphenyl)indium (4.0 mL, 0.05 M in THF, 0.2 mmol) was
added. The resulting mixture was heated at 80 °C until the inter-
mediate monocoupling product was consumed (16 h). The reac-
tion mixture was quenched and treated accordingly to the
general procedure to afford, after purification by column chrom-
atography (30% Et2O/hexanes), concentration and high vacuum
drying, the pyrimidine 6 (164 mg, 0.425 mmol, 85%) as a pale
yellow solid. Mp 139–140 °C; IR (ATR) 3055, 2961, 2852,
1
2866, 1559, 1444 cm−1; H NMR (300 MHz, CDCl3) δ 7.90 (s,
1 H), 7.80–7.87 (m, 2 H), 7.37–7.41 (m, 2 H), 6.97 (s, 1 H),
3.78–3.91 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ 161.6 (C),
161.2 (C), 160.8 (C), 142.2 (C), 141.1 (C), 139.8 (C), 126.1
(CH), 124.8 (CH), 124.7 (CH), 124.3 (CH), 122.6 (CH), 104.2
(CH), 66.8 (2 × CH2), 44.3 (2 × CH2); MS (EI) m/z 333 [M+]
(37Cl, 36), 331 [M+] (35Cl, 97); HRMS (EI) calcd for
C16H14ON3ClS 331.0541 [M+], found 331.0537.
4-(4-Chloro-6-cyclopropylpyrimidin-2-yl)morpholine (5f).
According to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with tri(cyclopropyl)indium (0.2 mmol) afforded,
after purification by column chromatography (10% Et2O/
hexanes), compound 5f as a white solid (84 mg, 70%). Mp
75–77 °C; IR (ATR) 3097, 2962, 2904, 2859, 1542, 1498,
1566, 1544, 1479, 2447 cm−1 1H NMR (300 MHz, CDCl3)
;
1446 cm−1 1H NMR (300 MHz, CDCl3) δ 7.64 (s, 1 H),
;
δ 8.23 (d, J = 8.2 Hz, 1 H), 8.11–8.14 (m, 2 H), 7.75 (d, J =
8.2 Hz, 2 H), 7.49–7.53 (m, 3 H), 7.44 (s, 1H), 3.82–4.11 (m,
8 H); 13C NMR (75 MHz, CDCl3) δ 165.8 (C), 163.8 (C), 162.3
3.69–3.81 (m, 8 H), 1.71–1.82 (m, 1 H), 1.00–1.08 (m, 2 H),
0.93–0.99 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 174.2 (C),
161.4 (C), 160.4 (C), 107.2 (CH), 66.7 (2 × CH2), 44.2
(2 × CH2), 16.9 (CH), 10.6 (2 × CH2); MS (EI) m/z 241 [M+]
(37Cl, 16), 239 [M+] (35Cl, 46); HRMS (EI) calcd for
C11H14ON3Cl 239.0820 [M+], found 239.0817.
2
(C), 137.8 (C), 132.0 (q, JCF = 32.5 Hz, C), 130.6 (CH), 127.7
3
(2 × CH), 127.4 (2 × CH), 127.1 (2 × CH), 125.6 (q, JCF
=
1
3.9 Hz, 2 × CH), 124.0 (q, JCF = 272.0 Hz, CF3), 102.5 (CH),
67.0 (2 × CH2), 44.4 (2 × CH2); MS (EI) m/z 386 [M+ + 1] (16),
385 [M+] (65), 354 (100); HRMS (EI) calcd for C21H18ON3F3
385.1396 [M+], found: 385.1398.
4-[4-Chloro-6-(phenylethynyl)pyrimidin-2-yl]morpholine (5g).
According to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with tri(phenylethynyl)indium (0.2 mmol) afforded,
after purification by column chromatography (10% Et2O/
hexanes), compound 5g as a pale yellow solid (69 mg, 46%).
Mp 100–102 °C; IR (ATR) 2945, 2920, 2869, 2215, 1603, 1553,
4-[4-(Naphthalen-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-
2-yl]morpholine (7). According to the general procedure, the
reaction of 5c (163 mg, 0.5 mmol) with tri(4-trifluoromethyl-
phenyl)indium (0.2 mmol) afforded, after purification by column
chromatography (30% Et2O/hexanes), compound 7 as a orange
solid (152 mg, 70%). Mp 174–176 °C; IR (ATR) 3049, 2962,
;
1527, 1492, 1446 cm−1 1H NMR (300 MHz, CDCl3)
δ 7.58–7.61 (m, 2 H), 7.38–7.41 (m, 3 H), 6.73 (s, 1H),
3.83–3.87 (m, 4 H), 3.74–3.78 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ 161.4 (C), 161.2 (C), 152.3 (C), 132.4 (2 × CH),
129.8 (CH), 128.5 (2 × CH), 121.3 (C), 111.8 (CH), 92.6 (C),
86.8 (C), 66.7 (2 × CH2), 44.3 (2 × CH2); MS (EI) m/z 301 [M+]
(37Cl, 29), 299 [M+] (35Cl, 86); HRMS (EI) calcd for
C16H14ON3Cl 299.0820 [M+], found 299.0817.
2895, 2853, 1559, 1539, 1445 cm−1 1H NMR (300 MHz,
;
CDCl3) δ 8.31–8.35 (m, 1 H), 8.23 (d, J = 8.2 Hz, 2 H),
7.93–7.99 (m, 2 H), 7.74–7.77 (m, 2 H), 7.53–7.56 (m, 4 H),
7.31 (s, 1 H), 3.84–4.05 (m, 8 H); 13C NMR (75 MHz, CDCl3)
δ 168.4 (C), 163.2 (C), 162.1 (C), 141.3 (C), 137.2 (C), 134.0
2
(C), 132.6 (q, JCF = 32.5 Hz, C), 130.7 (C), 129.9 (CH), 128.5
(CH), 127.5 (2 × CH), 127.3 (CH), 126.6 (CH), 126.1 (CH),
3
(E)-4-(4-Chloro-6-styrylpyrimidin-2-yl)morpholine (5h).
According to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with tri(β-styryl)indium (0.2 mmol) afforded, after
purification by column chromatography (5% Et2O/hexanes),
compound 5h as a pale yellow solid (63 mg, 42%). Mp
125.6 (q, JCF = 3.9 Hz, 2 × CH), 125.5 (CH), 125.3 (CH),
1
124.0 (q, JCF = 272.3 Hz, CF3), 107.4 (CH), 67.0 (2 × CH2),
44.4 (2 × CH2); MS (EI) m/z 435 [M+] (68), 404 (100); HRMS
(EI) calcd for C25H20ON3F3 435.1553 [M+], found: 435.1551.
86–88 °C; IR (ATR) 2963, 2896, 2855, 1553, 1524, 1445 cm−1
;
4-[4-[(2,2′-Bithiophen)-5-yl]-6-(naphthalen-1-yl)pyrimidin-2-yl]-
morpholine (8). According to the general procedure, the reaction
of 5c (163 mg, 0.5 mmol) with tri(2,2′-bithiophen-5-yl)indium
(0.2 mmol) afforded, after purification by column chromato-
graphy (30% Et2O/hexanes), compound 8 as a yellow solid
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 16.0 Hz, 1 H),
7.56–7.59 (m, 2 H), 7.35–7.41 (m, 3 H), 6.90 (d, J = 16.0 Hz,
1 H), 6.60 (s, 1 H), 3.74–3.90 (m, 8 H); 13C NMR (75 MHz,
CDCl3) δ 164.3 (C), 161.6 (C), 161.3 (C), 137.1 (CH), 135.7
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9045–9051 | 9049

View Article Online
(180 mg, 79%). Mp 157–158 °C; IR (ATR) 3074, 2957, 2917,
2864, 1563, 1535, 1479, 1459, 1445 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.31–8.34 (m, 1 H), 7.92–7.97 (m, 2 H), 7.22 (d, J =
7.0 Hz, 1 H), 7.51–7.62 (m, 4 H), 7.27–7.32 (m, 2 H), 7.21 (d,
J = 3.9 Hz, 1 H), 7.15 (s, 1 H), 7.07 (t, J = 4.4 Hz, 1 Hz),
3.83–3.86 (m, 4 H), 3.97–4.00 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ 167.6 (C), 161.7 (C), 159.2 (C), 142.3 (C), 141.0 (C),
137.3 (2 × C), 134.0 (C), 130.8 (C), 129.7 (CH), 128.5 (CH),
128.0 (CH), 127.4 (CH), 127.2 (CH), 126.5 (CH), 126.0 (CH),
125.6 (CH), 125.3 (2 × CH), 124.5 (2 × CH), 105.2 (CH), 67.0
(2 × CH2), 44.4 (2 × CH2); MS (EI) m/z 455 [M+] (100); HRMS
(EI) calcd for C26H21ON3S2 455.1121 [M+], found: 455.1118.
99.5 (CH), 67.0 (2 × CH2), 44.2 (2 × CH2); MS (EI): m/z
380 [M+ + 1] (23), 379 [M+] (98); HRMS (EI) calcd for
C20H17N3OS2 379.0808 [M+], found: 379.410811.
4-[4-[(2,2′-Bithiophen)-5-yl]-6-(benzo[b]thiophen-2-yl)pyrimidin-
2-yl]morpholine (12). According to the general procedure, the
reaction of 5e (166 mg, 0.5 mmol) with tri(2,2′-bithiophen-2-yl)-
indium (0.2 mmol) afforded, after purification by column
chromatography (30% Et2O/hexanes), compound 12 as a yellow-
green solid (170 mg, 74%). Mp 181–183 °C; IR (ATR) 3068,
2956, 2922, 2852, 1564, 1543 cm−1 1H NMR (300 MHz,
;
CDCl3) δ 8.03 (s, 1 H), 7.84–7.90 (m, 2 H), 7.69 (d, J = 3.9 Hz,
1 H), 7.39 (dd, J = 3.3, 2.4 Hz, 2 H), 7.28–7.32 (m, 3 H),
7.21–7.24 (m, 1 H), 7.07 (dd, J = 5.1, 3.6 Hz, 1 H), 3.84–3.87
(m, 4 H), 3.95–4.00 (m, 4 H); 13C NMR (75 MHz, CDCl3)
δ 161.5 (C), 159.9 (C), 159.5 (C), 143.9 (C), 142.1 (C), 141.0
(C), 140.0 (C), 137.2 (C), 128.0 (CH), 127.4 (CH), 125.7 (CH),
125.3 (CH), 124.6 (CH), 124.5 (CH), 124.4 (CH), 123.3 (CH),
122.6 (CH), 99.1 (CH), 67.0 (2 × CH2), 44.3 (2 × CH2); MS
(EI) m/z 461 [M+ + 1] (100), 460 [M+] (20); HRMS (EI) calcd
for C24H19ON3S3 461.0685 [M+], found: 461.0677.
4-[4-[(2,2′-Bithiophen)-5-yl]-6-(thiophen-2-yl)pyrimidin-2-yl]-
morpholine (9). According to the general procedure, the reaction
of 5d (141 mg, 0.5 mmol) with tri(2,2′-bithiophen-5-yl)indium
(0.2 mmol) afforded, after purification by column chromato-
graphy (30% Et2O/hexanes), compound 9 as a yellow solid
(165 mg, 80%). Mp 174–175 °C; IR (ATR) 3070, 2958, 2923,
2853, 1563, 1542 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.75 (d,
J = 3.6 Hz, 1 H), 7.64 (d, J = 3.8 Hz, 1 H), 7.47 (dd, J = 5.0,
1.1 Hz, 1 H), 7.27–7.30 (m, 2 H), 7.18–7.21 (m, 1 H),
7.13–7.16 (m, 2 H), 7.06 (dd, J = 5.2, 3.6 Hz, 1 H), 3.82–3.85
(m, 4 H), 3.93–3.96 (m, 4 H); 13C NMR (75 MHz, CDCl3)
δ 161.5 (C), 159.7 (C), 159.5 (C), 143.8 (C), 142.2 (C), 140.8
(C), 137.3 (C), 129.0 (CH), 128.0 (2 × CH), 127.2 (CH), 126.6
(CH), 125.2 (CH), 124.4 (2 × CH), 98.5 (CH), 67.0 (2 × CH2),
44.2 (2 × CH2); MS (EI) m/z 412 [M+ + 1] (44), 411 [M+] (99);
HRMS (EI) calcd for C20H17ON3S3 411.0528 [M+], found
411.0525.
4-[4-(Cyclopropyl-6-(furan-2-yl-)pyrimidin-2-yl]morpholine
(13). According to the general procedure, the reaction of 5f
(120 mg, 0.5 mmol) with tri(fur-2-yl)indium (0.2 mmol)
afforded, after purification by column chromatography (20%
Et2O/hexanes), compound 13 as a pale yellow solid (88 mg,
65%). Mp 91–93 °C; IR (ATR) 3068, 2957, 2922, 2852, 2359,
1732, 1602, 1558, 1545 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 7.52 (dd, J = 1.8, 0.8 Hz, 1 H), 7.11 (dd, J = 3.4, 0.8 Hz, 1 H),
6.81 (s, 1 H), 6.51 (dd, J = 3.4, 1.8 Hz, 1 H), 3.73–3.83 (m,
8 H), 1.86–1.93 (m, 1 H), 1.08–1.11 (m, 2 H), 0.95–0.98 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 172.9 (C), 161.1 (C), 155.0
(C), 153.0 (C), 144.0 (C), 112.0 (CH), 110.7 (CH), 102.2 (CH),
67.0 (2 × CH2), 44.2 (2 × CH2), 17.2 (CH), 10.1 (2 × CH2); MS
(EI) m/z 271 [M+] (76), 240 (100); HRMS (EI) calcd for
C15H17O2N3 271.1315 [M+], found: 271.1315.
4-[4-(Pyrimidin-2-yl)-6-(thiophen-2-yl)pyrimidin-2-yl]morpholine
(10). According to the general procedure, the reaction of 5d
(141 mg, 0.5 mmol) with tri(pyridin-2-yl)indium (0.2 mmol)
afforded, after purification by column chromatography (30–50%
Et2O/hexanes), compound 10 as a pale yellow solid (107 mg,
66%). Mp 148–150 °C; IR (ATR) 2961, 2864, 1565, 1548,
1
1487 cm−1; H NMR (300 MHz, CDCl3) δ 8.75 (d, J = 4.7 Hz,
4-[4,6-Bis(benzo[b]thiophen-2-yl)pyrimidin-2-yl]morpholine
(14). According to the general procedure, the reaction of 4
(117 mg, 0.5 mmol) with tri(thiophen-2-yl)indium (0.35 mmol)
afforded, after purification by column chromatography (10%
Et2O/hexanes), compound 14 as a pale yellow solid (150 mg,
91%). Mp 161–162 °C; IR (ATR) 3091, 2956, 2893, 2855,
1 H), 8.44 (d, J = 7.9 Hz, 1 H), 8.00 (s, 1 H), 7.84–7.89 (m,
2 H), 7.38–7.50 (m, 2 H), 7.16 (dd, J = 5.0, 3.8 Hz, 1 H),
3.84–4.00 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ 163.7 (C),
161.8 (C), 160.6 (C), 154.9 (C), 149.0 (CH), 143.9 (C), 137.0
(CH), 129.1 (CH), 128.1 (CH), 127.2 (CH), 125.0 (CH), 121.6
(CH), 101.4 (CH), 67.0 (2 × CH2), 44.4 (2 × CH2); MS
(ESITOF) m/z 325 [M+ + H] (100); HRMS (ESITOF) calcd for
C17H17ON4S 325.1117 [M+ + H], found 325.1125.
1
1538, 1450 cm−1; H NMR (300 MHz, CDCl3) δ 7.76 (dd, J =
3.8, 1.1 Hz, 2 H), 7.48 (dd, J = 5.0, 1.1 Hz, 2 H), 7.19 (s, 1 H),
7.15 (dd, J = 5.0, 3.8 Hz, 2 H), 3.80–4.00 (m, 8 H); 13C NMR
(75 MHz, CDCl3) δ 161.6 (C), 159.8 (C), 143.8 (C), 129.0
(CH), 128.0 (CH), 126.5 (CH), 98.8 (CH), 67.0 (2 × CH2), 44.2
(2 × CH2); MS (EI) m/z 329 [M+] (100); HRMS (EI) calcd for
C16H15N3OS2 329.0651 [M+], found: 329.0641.
4-[4-(Benzo[b]thiophen-2-yl)-6-(thiophen-2-yl)pyrimidin-2-yl]-
morpholine (11). According to the general procedure, the reac-
tion of 5e (166 mg, 0.5 mmol) with tri(thiophen-2-yl)indium
(0.2 mmol) afforded, after purification by column chromato-
graphy (15% Et2O/hexanes), compound 11 as a lemon yellow
solid (139 mg, 73%). Mp 147–149 °C; IR (ATR) 2958, 2922,
2853, 1560, 1542 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.01 (d,
J = 0.69 Hz, 1 H), 7.82–7.89 (m, 2 H), 7.79 (dd, J = 3.8 Hz,
1 H), 7.49 (dd, J = 5.0 Hz, 1 H), 7.36–7.41 (m, 2 H), 7.30 (s,
1 H), 7.17 (dd, J = 5.0 Hz, 1 H), 3.83–3.99 (m, 8 H); 13C NMR
(75 MHz, CDCl3) δ 161.6 (C), 159.9 (2 × C), 143.9 (C), 143.7
(C), 140.9 (C), 140.0 (C), 129.2 (CH), 128.1 (CH), 126.7 (CH),
125.7 (CH), 124.6 (CH), 124.5 (CH), 123.3 (CH), 122.6 (CH),
4-[4,6-Di(thiophen-2-yl)pyrimidin-2-yl]morpholine (15).
According to the general procedure, the reaction of 4 (117 mg,
0.5 mmol) with tri(benzo[b]thiophen-2-yl)indium (0.35 mmol)
afforded, after purification by column chromatography (10%
Et2O/hexanes), compound 15 as a yellow solid (204 mg, 95%).
Mp 238–240 °C; IR (ATR) 3059, 2957, 2922, 2867, 1544,
1
1496 cm−1; H NMR (300 MHz, CDCl3) δ 8.05 (broad s, 2 H),
7.84–7.88 (m, 4 H), 7.45 (s, 1 H), 7.38–7.41 (m, 4 H),
9050 | Org. Biomol. Chem., 2012, 10, 9045–9051
This journal is © The Royal Society of Chemistry 2012

View Article Online
3.84–4.01 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ 161.5 (C),
160.0 (C), 143.8 (C), 141.0 (C), 140.0 (C), 125.7 (CH), 124.6
(CH), 124.5 (CH), 123.4 (CH), 122.6 (CH), 100.1 (CH), 66.9 (2
× CH2), 44.2 (2 × CH2); MS (EI) m/z 429 [M+] (90), 398 (100);
HRMS (EI) calcd for C24H19N3OS2 429.0964 [M+], found:
429.0955.
X. Xin, D. Menezes, H. Merritt, I. Lee, M. Wiesmann, S. Kaufman,
K. Crawford, M. Chin, D. Bussiere, K. Shoemaker, I. Zaror, S.-M. Maira
and C. F. Voliva, ACS Med. Chem. Lett., 2011, 2, 774–779;
(b) A. D. William, A. C.-H. Lee, K. C. Goh, S. Blanchard, A. Poulsen,
E. L. Teo, H. Nagaraj, C. P. Lee, H. Wang, M. Williams, E. T. Sun,
C. Hu, R. Jayaraman, M. K. Pasha, K. Ethirajulu, J. M. Wood and
B. W. Dymock, J. Med. Chem., 2012, 169–196.
5 C. Zdenko, S. Miha and K. Janez, J. Org. Chem., 2010, 75, 6681–6684.
6 (a) A. Turck, N. Plé, F. Mongin and G. Quéguiner, Tetrahedron, 2001,
57, 4489–4505; (b) T. J. Delia and A. Nagarajan, J. Heterocycl. Chem.,
1998, 35, 269–273; (c) J. M. Schomaker and T. J. Delia, J. Heterocycl.
Chem., 2000, 37, 1457–1462; (d) Y. M. Loksha, D. Globisch, R. Loddo,
G. Collu, P. La Colla and E. B. Pedersen, ChemMedChem, 2010, 5,
1847–1849.
7 (a) S. Schröter, C. Stock and T. Bach, Tetrahedron, 2005, 61, 2245–2267;
(b) I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036–1045; (c) R. Rossi,
F. Bellina and M. Lessi, Adv. Synth. Catal., 2012, 354, 1181–1255.
8 (a) J. M. Schomaker and T. J. Delia, J. Org. Chem., 2001, 66, 7125–
7128; (b) G. A. Molander, B. W. Katona and F. Machrouhi, J. Org.
Chem., 2002, 67, 8416–8423.
9 (a) I. Pérez, J. Pérez Sestelo and L. A. Sarandeses, Org. Lett., 1999, 1,
1267–1269; (b) I. Pérez, J. Pérez Sestelo and L. A. Sarandeses, J. Am.
Chem. Soc., 2001, 123, 4155–4160; (c) M. A. Pena, J. Pérez Sestelo and
L. A. Sarandeses, Synthesis, 2003, 780–784; (d) J. Caeiro, J. Pérez
Sestelo and L. A. Sarandeses, Chem.–Eur. J., 2008, 14, 741–746;
(e) R. Riveiros, L. Saya, J. Pérez Sestelo and L. A. Sarandeses,
Eur. J. Org. Chem., 2008, 1959–1966.
10 (a) M. Rega, P. Candal, C. Jiménez and J. Rodríguez, Eur. J. Org. Chem.,
2007, 934–942; (b) A. Meyer, M. Bruenjes, F. Taft, T. Frenzel, F. Sasse
and A. Kirschning, Org. Lett., 2007, 9, 1489–1492; (c) M. Peña-López,
M. M. Martínez, L. A. Sarandeses and J. Pérez Sestelo, Chem.–Eur. J.,
2009, 15, 910–916.
11 (a) L. Bouissane, J. Pérez Sestelo and L. A. Sarandeses, Org. Lett., 2009,
11, 1285–1288; (b) M. M. Martínez, M. Peña-López, J. Pérez Sestelo and
L. A. Sarandeses, Org. Biomol. Chem., 2012, 10, 3892–3898;
(c) A. Mosquera, R. Riveiros, J. Pérez Sestelo and L. A. Sarandeses, Org.
Lett., 2008, 10, 3745–3748.
12 C. Guérémy, F. Audiau, C. Renault, J. Benavides, A. Uzan and G. L. Fur,
J. Med. Chem., 1986, 29, 1394–1398.
13 L. A. Wessjohann and W. Brandt, Chem. Rev., 2003, 103, 1625–1647.
14 A. Agarwal, K. Srivastava, S. K. Puri and P. M. S. Chauchan, Bioorg.
Med. Chem. Lett., 2005, 15, 1881–1883.
Acknowledgements
We are grateful to the Ministerio de Ciencia e Innovación (Spain,
CTQ2009-07180) and Xunta de Galicia (Spain, INCITE08P-
XIB103167PR) for financial support.
Notes and references
1 (a) D. J. Brown, in The Pyrimidines, ed. R. F. Evans, W. B. Cowden and
M. D. Fenn, John Wiley & Sons, UK, 1994; (b) D. J. Brown, in Com-
prehensive Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees,
Pergamon, Oxford (UK), 1984, ch. 2.13, vol. 3, pp. 57–155;
(c) K. Undheim and T. Benneche, in Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriben,
Elsevier, Oxford (UK), 1996, ch. 6.02, vol. 6, pp. 93–231; (d) M. Radi,
S. Schenone and M. Botta, Org. Biomol. Chem., 2009, 7, 2841–2847.
2 (a) G. Hughes, C. Wang, A. S. Batsanov, M. Fern, S. Frank,
M. R. Bryce, I. F. Perepichka, A. P. Monkman and B. P. Lyons, Org.
Biomol. Chem., 2003, 1, 3069–3077; (b) K. Itami, D. Yamazaki and
J.-I. Yoshida, J. Am. Chem. Soc., 2004, 126, 15396–15397;
(c) S. Achelle, Y. Ramondenc, F. Marsais and N. Plé, Eur. J. Org. Chem.,
2008, 3129–3140; (d) R. P. Ortiz, J. Casado, V. Hernández, J. T. López
Navarrete, J. A. Letizia, M. A. Ratner, A. Facchetti and T. Marks,
Chem.–Eur. J., 2009, 15, 5023–5039; (e) C. Hadad, S. Achelle,
J. C. García-Martínez and J. Rodríguez-López, J. Org. Chem., 2011, 76,
3837–3845; (f) I. Malik, Z. Ahmed, S. Reimann, I. Ali, A. Villinger and
P. Langer, Eur. J. Org. Chem., 2011, 2088–2093.
3 T. Brorowski, M. Król, E. Broclawik, T. C. Baranowski, L. Strekowski
and M. J. Mokrosz, J. Med. Chem., 2000, 43, 1901–1909 and references
therein.
4 (a) M. T. Burger, S. Pecchi, A. Wagman, Z.-J. Ni, M. Knapp,
T. Hendrickson, G. Atallah, K. Pfister, Y. Zhang, S. Bartulis, K. Frazier,
S. Ng, A. Smith, J. Verhagen, J. Haznedar, K. Huh, Ed. Iwanowicz,
15 R. F. Schinazi and L. Strekowiski, PCT Int. Appl., WO8911279, 1989.
16 Z.-H. Peng, M. Journet and G. Humphrey, Org. Lett., 2006, 8, 395–398.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9045–9051 | 9051