Regioselective halogenation of aminopyrimidinyl-pyrrole carboxylic acid derivatives

Article abstract of DOI:10.1016/j.tet.2009.10.030

The regioselective synthesis of halogenated aminopyrimidinyl-pyrroles as useful scaffolds for the preparation of diversified selective kinase inhibitors is described. The chemistry is simple and mostly based on the use of N-halosuccinimides under mild rea

Full text of DOI:10.1016/j.tet.2009.10.030

Tetrahedron 65 (2009) 10418–10423
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective halogenation of aminopyrimidinyl-pyrrole carboxylic acid
derivatives
a
a
b
a
b
a
`
Ermes Vanotti , Marina Caldarelli , Teresa Disingrini , Marcella Nesi , Marco Tato , Paola Vianello ,
Maria Menichincheri a
,
*
a Department of Medicinal Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (Mi), Italy
b Department of Chemical Core Technologies, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (Mi), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective synthesis of halogenated aminopyrimidinyl-pyrroles as useful scaffolds for the
preparation of diversified selective kinase inhibitors is described. The chemistry is simple and mostly
based on the use of N-halosuccinimides under mild reaction conditions but the regioselectivity observed
is partially unexpected.
Received 19 June 2009
Received in revised form
21 September 2009
Accepted 8 October 2009
Available online 13 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidine
Pyrrole
N-Halosuccinimide
Halogenation
Kinase inhibitors
1. Introduction
Our attention focused primarily on scaffold 1, characterized by
the aminopyrimidinyl-pyrrole nucleus, the halogenation of which
Nitrogen containing heterocyclic scaffolds are the focus of many
medicinal chemistry programs due to the great interest they arouse
for a wide range of biological targets, for example, protein kinase
inhibitors.1 Regioselective derivatization of such scaffolds consti-
tutes a common strategy for potency optimization against the
desired biological target, but also for selectivity improvement vs
a series of related targets whose inhibition might cause unwanted
toxic effects.2 To address and achieve such goals, the availability of
suitably reactive precursors is of crucial importance.
During the development of our medicinal chemistry programs,
novel heteroaryl-pyrrole scaffolds were shown to be useful tools to
identify potent and selective kinase inhibitors.3 In this respect,
a procedure to prepare selectively halogenated heteroaryl-pyrroles
would be extremely valuable, leading to intermediates that could
be further derivatized by palladium-mediated C–C and C–N bond
forming reactions under mild conditions.4,5
is the main subject of the present work. The chemistry involved is
straightforward and mostly based on the use of N-halosuccinimides
under mild reaction conditions 6,7 but the investigation led to some
interesting regioselectivity results that might be of relevance to
others.
O
R
3
4
5
5'
2
6'
4'
N
1'
N
H
N 3'
H2N
1a
1b
R = OEt
R = NH2
2. Results and discussion
Scaffold 1 was prepared as shown in Scheme 1 from commer-
* Corresponding author. Tel.: þ39 331 581928; fax: þ39 331 581347.
E-mail address: maria.menichincheri@nervianoms.com (M. Menichincheri).
cially available materials.8
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.030

E. Vanotti et al. / Tetrahedron 65 (2009) 10418–10423
10419
As iodoaromatics frequently show enhanced and uniquely high
reactivity as compared to their bromo and chloro analogues, we
were particularly interested in the preparation of 50-iodopyr-
imidine derivatives.11 Unfortunately, despite our efforts in trying
both different sources of electrophilic iodine and reaction condi-
tions, we were not able to find a gratifying solution. Generally
speaking, we found, working on both 1 and related scaffolds, that,
although formation of the iodopyrrole is usually favoured, iodin-
ation of the 50-pyrimidine position is more likely to compete either
when an alkyl substituent on the pyrrole nitrogen is present
(i.e., methyl, ethyl, 2,2,2-trifluoro-ethyl, easily cleavable 2-(trime-
thylsilyl)ethoxymethyl) or by employing a strong source of positive
iodine such as trifluoroacetyl hypoiodite in DMF at low tempera-
tures. Further elucidation in order to better exploit the use of
protecting groups on the pyrrole nitrogen (i.e., 2-(trimethylsily-
l)ethoxymethyl) to re-orient the iodination reaction on the
aminopyrimidine nucleus is still on-going. Direct iodination of 1b
by employing trifluoroacetyl hypoiodite generated in situ from
iodine and silver trifluoroacetate in DMF at ꢁ40 ꢀC gave poor
results, generating a 1:1 mixture of 6b and 5b (Scheme 2). However,
easy separation by flash chromatography under standard condi-
tions of the reaction mixture was feasible and compound 6b was
isolated with 15% yield. Under the same conditions, better results
were obtained when the ester 5a was employed as in this case
isolation yield of compound 6a was higher (50%).
O
COOEt
a, b
c, d
+
1a
1b
O
N
N
Br
NH2
2
Scheme 1. (a) NaH, THF, DMF, 0 ꢀC-rt; (b) NH4OAc, EtOH, rt, (46% from 2); (c) NaOH,
EtOH, 100 ꢀC; (d) HOBt$NH3, DIPEA, EDCI$HCl, THF, rt, (43%).
The key step of the synthesis is based on the Hantzsch reaction
that accesses the tri-substituted pyrrole frame. Bromoketone 2 was
allowed to react with the sodium enolate of ethyl 3-oxo-3-phenyl-
propanoate in the presence of ammonium acetate, yielding ester 1a
thatwastransformed, viathecarboxylicacid, intotheprimaryamide
1b by means of hydroxybenzotriazole ammonium salt in the pres-
ence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDCI$HCl). As mentioned above, scaffold 1 is an interesting
substrate for halogenations. When 1a was exposed to halogenation
with equimolar amounts of N-chlorosuccinimide or N-bromo-
succinimide, analogues 3a and 4a, mono-halogenated at position 50
of the pyrimidine ring, were respectively obtained (Scheme 2).
O
O
R
R
I
Cl
Halogenation of 1b could also be re-oriented on the pyrrole
nucleus by deactivation of the pyrimidine ring with electron-
withdrawing protections at the amino group. When 1b was
protected at the aminopyrimidine nucleus as N,N-di-tertbutoxy-
carbonyl derivative, it was transformed into chloropyrrole 9b by
treatment with N-chlorosuccinimide at 100 ꢀC in DMF, followed by
removal of the protection under acidic conditions (Scheme 3).
N
H
N
H
N
N
N
N
d
c
a
b
6a (50%)
6b (15%)
3a (58%)
3b (72%)
H2N
H2N
1a-b
O
O
R
I
R
Br
N
H
N
H
N
N
N
N
CONH2
CONH2
5a (64%)
5b (72%)
4a (65%)
4b (75%)
H2N
H2N
a
N
H
N
H
Scheme 2. (a) NCS (1 equiv), DMF, 60–80 ꢀC; (b) NBS (1 equiv), DMF, rt; (c) NIS
(1 equiv), DMF, rt; (d) CF3COOAg, I2, DMF, ꢁ40 ꢀC, (5a–bþ6a–b: chromatographic
separation).
N
N
N
N
H2N
N(Boc)2
1b
7b
This transformation occurred in DMF, under heating in the first
case or at room temperature in the second, reflecting the different
reactivity of the two reagents imposed mainly by their different bond
energies (N–Cl>N–Br). Moreover, halogenation of aromatic com-
poundswithNXSinapolarsolventsuchasDMFisexpectedtoproceed
via aromatic electrophilic substitution with the electrophile attacking
the most electron-rich and less sterically encumbered 2-amino-py-
rimidine ring. In a similar fashion, we and others have already de-
scribedthe brominationattheC-50 positionof the2-aminopyrimidine
ring in systems such as 2-(2-aminopyrimidin-4-yl)-pyrazolo-
pyridinones and 3-(2-aminopyrimidin-4-yl)-indoles by employing
N-bromosuccinimide.3a,9 Interestingly, halogenation could be
oriented on the pyrrole nucleus by using equimolar N-iodosuccini-
mide that converted 1a into iodopyrrole 5a in DMF at room temper-
ature. This rather unexpected result prompted us to carry out further
investigations. Similarly, whentheprimaryamide1bwas treated with
an equimolar amount of N-chlorosuccinimide or N-bromosuccini-
mide, analogues 3b and 4b, mono-halogenated at position 50 of the
pyrimidine ring, were obtained whereas an equimolar amount of
N-iodosuccinimide produced the iodopyrrole 5b,10 thus confirming
the selectivity pattern observed on the ester 1a. The larger size and
lowerpositivechargedensityofiodine, comparedtobothchlorineand
bromine, seems to suggest that the observed regiochemistry is
modulated by the nucleophilic carbon attack to the halogen, with the
most reactive C-50 pyrimidine position reacting with chlorine and
bromine and the less reactive C-4 pyrrole one with iodine.
b
Cl
Cl
CONH2
CONH2
c
N
N
H
N
N
H
N
N
H2N
N(Boc)2
9b
8b
Scheme 3. (a) (Boc)2O, THF, rt, chromatographic separation from mono- and tri-Boc
derivatives, (14%); (b) NCS (1 equiv), DMF, 100 ꢀC, (45%); (c) HCl in dioxane, 50 ꢀC,
(82%).
Furthermore, multiple halogenations take place on compound
1b, both in a double-sequential and double-simultaneous mode. In
fact, when bromopyrimidine 4b was treated with equimolar N-
iodosuccinimide compound 10b was obtained. The same product
was also formed upon treatment of iodopyrrole 5b with equimolar
amounts of N-bromosuccinimide (Scheme 4).
I
CONH2
Br
a
b
N
H
N
4b
5b
N
10b
H2N
Scheme 4. (a) NIS (1 equiv), DMF, rt, (82%); (b) NBS (1 equiv), DMF, rt, (83%).

10420
E. Vanotti et al. / Tetrahedron 65 (2009) 10418–10423
In this way, differential reactivity was achieved on the two rings,
acetonitrile 90:10, and mobile phase B was ammonium acetate
5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; the gra-
dient was from 0 to 100% B in 7 min then hold 100% B for 2 min
before equilibration. 1H and 13C NMR spectra were acquired at 25 ꢀC
in DMSO-d6 on a Varian Inova 500 spectrometer equipped with
5 mm 1H{13C,15N} z-axis-PFG Triple Resonance Cold Probe and on
a Varian Inova 400 spectrometer equipped with 5 mm 1H{15N-
31P} z-axis-PFG Indirect Detection probe. Residual not-deuterated
useful for directing further synthetic elaborations.12 When the
same approach was used to brominate 6b, both at room tempera-
ture and at ꢁ20 ꢀC, a complex mixture was obtained, where 4b and
10b were detected as major components and no trace could be
found of the expected 50-iodo-pyrimidinyl-4-bromopyrrole
derivative.13 On the other hand, compound 1b was simultaneously
dihalogenated to 11b or 12b, upon treatment with two equivalents
of the proper N-halosuccinimide (Scheme 5).
solvent signal was used as reference (
d
¼2.50 ppm for 1H and
d
¼39.5 for 13C). Two-dimensional pulse sequences (T-Roesy, gra-
dient-enhanced with adiabatic pulses HSQC and HMBC) provided
by the standard Varian software Vnmrj 2.1B were used to assign
carbons and regiochemistry. Low-resolution mass spectral (MS)
data were determined on a Finnigan MAT LCQ ion trap instrument,
equipped with ESI ion source and mass values are given as an m/z
ratio. ESI(þ) high-resolution mass spectra (HRMS) were obtained
on a Waters Q-Tof Ultima directly connected with micro HPLC 1100
Agilent as previously described.15 IR spectra of powders were
recorded on a Thermo Scientific Nicoloet iS10 instrument equipped
with an ATR SMART ENDURANCE (nmax in cmꢁ1). Chromatographic
purification was performed either under medium pressure on silica
Br
I
CONH2
CONH2
I
Br
a
b
N
H
N
H
N
N
1b
N
N
11b
12b
H2N
H2N
Scheme 5. (a) NBS (2 equiv), DMF, rt, (90%); (b) NIS (2 equiv), DMF, rt, (46%).
These compounds, bearing multiple identical halogens, though
appealing, are subjected to a not easily predictable regioselectivity
rank, when subjected to cross-coupling reactions.14
(Merck silica gel 40ꢁ63
mm) or on prepacked silica gel cartridges
The positions of the halogen atoms on the amino-pyrimidine or
on the pyrrole ring were unambiguously determined by NMR
spectroscopy. 1H and 13C NMR spectroscopic signals were assigned
by means of literature data and 2D experiments (1H–13C HSQC and
HMBC). The two aromatic protons of the aminopyrimidine ring give
(Biotage) or on a Horizon system. Thin-layer chromatography was
performed on Merck silica gel 60 plates coated with 0.25 mm layer
with fluorescent indicator. Components were visualized by UV light
(
l
¼254 and 366 nm) and iodine vapors. Melting points were de-
3
termined in an open capillary and are uncorrected.
rise to two typical doublets with JHH¼5.2 Hz around 7.3 and
8.3 ppm and the hetero-aromatic proton of the pyrrole ring is
a doublet with 4JH–NH¼2.7 Hz around 7.3–7.6 ppm. Halogenation on
position 50 of the aminopyrimidine ring is indicated by the disap-
pearance of the two doublets and the appearance of a singlet above
8.3 ppm, while the halogenation on position 4 of the pyrrole ring is
4.2. Synthesis
4.2.1. 5-(2-Amino-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-carbox-
amide 1b. 4.2.1.1. Step 1. To a solution of ethyl 3-oxo-3-phenyl-
propanoate (1.34 g, 7 mmol) in anhydrous THF (100 mL) at 0 ꢀC,
NaH (60% suspension in oil, 0.7 g, 17.5 mmol) was added under
argon with stirring. After 5 min 1-(2-amino-pyrimidin-4-yl)-2-
bromo-ethanone hydrobromide 2 (2.5 g, 8.4 mmol) was added and
the mixture was stirred at room temperature for 3 h. Solvent was
evaporated, the residue was dissolved in ethanol (65 mL), ammo-
nium acetate (1.6 g, 21 mmol) was added and the solution was
stirred at rt overnight. Solvent was evaporated to dryness and the
residue was purified by flash chromatography (EtOAc/n-hexane
7:3), yielding ethyl 5-(2-amino-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 1a (990 mg, 46%) as a yellowish powder, mp
157–160 ꢀC.
4
indicated by the disappearance of the doublet with JH–NH¼2.7 Hz
around 7.3–7.6 ppm. In the case of two different halogens on the
two heterocyclic rings, e.g., bromine on position 50 of the amino-
pyrimidine and iodine on position 4 of the pyrrole ring, their rel-
ative positions were determined by comparing the 13C chemical
shift of the corresponding quaternary carbons (obtained by 1H–13
C
HMBC) with the data of the mono-halogenated products and with
literature data.
3. Conclusion
The preparation of halogenated aminopyrimidinyl-pyrroles as
useful intermediates for the synthesis of novel biologically active
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.19 (t, J¼7.1 Hz, 3H) 4.12
compounds is described. The chemistry allows
a versatile
(q, J¼7.1 Hz, 2H) 6.44 (s, 2H) 7.09 (d, J¼5.2 Hz, 1H) 7.31 (d, J¼2.4 Hz,
1H) 7.38–7.48 (m, 3H) 7.62 (dd, J¼7.9, 1.6 Hz, 2H) 8.22 (d, J¼5.2 Hz,
1H) 12.00 (br s, 1H); 13C NMR (125 MHz, DMSO-d6): 13.8, 59.2,
112.2, 116.0, 118.4, 126.2, 126.8 (2C), 127.5, 128.3 (2C), 130.8, 136.4,
157.8,158.2,163.5, 164.8; IR 1450,1548,1566,1670,1691, 3186, 3362
nmax cmꢁ1; LCMS (ESI) m/z 309 (MþH)þ; HRMS (ESI) calcd for
C17H16N4O2þHþ 309.1346, found 309.135.
diversification of two key positions of the molecule, i.e., 50-pyrim-
idine and 4-pyrrole. Further decoration of the halogenated scaffolds
by means of the wide array of metal-catalyzed cross-coupling
reactions currently available will be described in due course.
4. Experimental
4.1. General
4.2.1.2. Step 2. To a suspension of ester 1a (3.65 g, 11.8 mmol) in
95% EtOH (45 mL), 4 M aqueous NaOH (45 mL) was added and the
mixture was refluxed for 5 h. Most solvent was evaporated and the
residue, cooled in ice bath, was acidified to pH 5 with concentrated
HCl. The precipitate was filtered, washed with little cold water, and
dried. 5-(2-Amino-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-carbox
ylic acid, obtained as a white solid (3.5 g), was used in the next step
without further purifications.
Purity was routinely measured by HPLC on a Waters X Terra RP
18 (4.6ꢂ50 mm, 3.5
mm) column using an SSP4000 (Thermo Sep-
aration Products) HPLC system equipped with an autosampler LC
Pal (CTC Analytics) and UV6000LP diode array detector (UV de-
tection 215–400 nm) and a Finnigan LCQ ion trap mass spectrom-
eter equipped with an electrospray (ESI) ion source. Instrument
control, data acquisition and processing were performed by using
Xcalibur 1.2 software (Finnigan). HPLC chromatography was run at
room temperature, and 1 mL/min flow rate. Mobile phase A was
ammonium acetate 5 mM buffer (pH 5.5 with acetic acid):
1H NMR (400 MHz, DMSO-d6)
d ppm 7.05 (br s, 2H) 7.22 (d,
J¼5.7 Hz, 1H) 7.37–7.48 (m, 4H) 7.63 (dd, J¼7.9, 1.7 Hz, 2H) 8.24 (d,
J¼5.9 Hz, 1H) 11.99 (br s, 1H) 12.10 (br s, 1H); LCMS (ESI) m/z 279
(MꢁH)ꢁ.

E. Vanotti et al. / Tetrahedron 65 (2009) 10418–10423
10421
4.2.1.3. Step 3. To a suspension of the acid (4 g, 14.3 mmol) in
anhydrous THF (80 mL), DIPEA (5.5 g, 42.9 mmol) and anhydrous
DMF (8 mL), cooled in ice bath and under stirring, hydroxy-
benzotriazole ammonium salt (HOBT$NH3, 3.26 g, 21.4 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI, 4.1 g, 21.4 mmol) were added. The reaction mixture
was stirred at room temperature overnight then it was poured
into a stirred 1:1 mixture of water and EtOAc. The organic phase
was washed with water, the aqueous layer was extracted with
EtOAc and the combined organic layers were washed with water,
dried over anhydrous Na2SO4 and concentrated, affording the
title compound as a precipitate that was filtered and washed
with little cold MeOH. The mother liquor was purified by flash
chromatography (DCM/MeOH/acetone 9:1:1), affording the de-
sired amide. The two product batches were combined, yielding
the title compound (1.71 g, 43%) as an orange powder, mp
225–228 ꢀC.
The title compound was obtained (27 mg, 64%) as a yellowish solid,
mp 136 ꢀC.
1H NMR (500 MHz, DMSO-d6)
d
ppm 1.07 (t, J¼7.1 Hz, 3H) 4.10
(q, J¼7.1 Hz, 2H) 6.56 (br s, 2H) 7.30 (d, J¼5.2 Hz, 1H) 7.37–7.49 (m,
5H) 8.32 (d, J¼5.2 Hz, 1H) 12.13 (br s, 1H); 13C NMR (125 MHz,
DMSO-d6): 13.6, 59.5, 67.0, 107.0, 127.7 (2C), 125.9, 128.0, 128.7 (2C),
130.8, 131.1, 138.6, 157.1, 158.3, 163.4, 164.0; IR 1430, 1456, 1563,
1636, 1698, 3141, 3293 nmax cmꢁ1; LCMS (ESI) m/z 435 (MþH)þ;
HRMS (ESI) calcd for C17H15IN4O2þHþ 435.0312, found 435.0308.
With similar procedures and starting from amide 1b, the fol-
lowing compounds were obtained.
4.2.5. 5-(2-Amino-5-chloro-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-
carboxamide 3b. 100 ꢀC, 18 h, 72% yield, off white powder, mp 257–
260 ꢀC. 1H NMR (400 MHz, DMSO-d6): 6.62 (br s, 2H), 6.88 (br s,
1H), 7.40 (br s, 1H), 7.33–7.39 (m, 1H), 7.39–7.47 (m, 2H), 7.58 (d,
J¼2.6 Hz, 1H), 7.63–7.69 (m, 2H), 8.27 (s, 1H), 11.27 (br s, 1H); 13C
NMR (125 MHz, DMSO-d6): 112.5, 116.1, 118.5, 126.2, 127.8 (2C),
128.1, 129.2 (2C), 131.4, 136.5, 152.2, 158.5, 161.5, 166.2; IR 1442,
1H NMR (400 MHz, DMSO-d6)
d ppm 6.36 (s, 2H) 6.82 (br s, 1H)
7.02 (d, J¼5.2 Hz, 1H) 7.27 (d, J¼2.6 Hz, 1H) 7.32 (br s, 1H) 7.32–7.37
(m, 1H) 7.37–7.44 (m, 2H) 7.64 (dd, J¼8.3, 1.3 Hz, 2H) 8.20 (d,
J¼5.2 Hz, 1H) 11.63 (br s, 1H); 13C NMR (125 MHz, DMSO-d6): 106.2,
116.1, 118.4, 126.2, 126.7 (2C), 127.5, 128.2 (2C), 130.7, 136.5, 157.8,
1452, 1538, 1557, 1585, 1620,1646, 3166, 3362, 3481 nmax cmꢁ1
;
LCMS (ESI) m/z 314 (MþH)þ; HRMS (ESI) calcd for C15H12ClN5OþHþ
314.0803, found 314.0802.
158.2, 163.4, 167.8; IR 1456, 1480, 1557, 1643, 3117, 3317 nmax cmꢁ1
;
LCMS (ESI) m/z 280 (MþH)þ; HRMS (ESI) calcd for C15H13N5OþHþ
4.2.6. 5-(2-Amino-5-bromo-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-
carboxamide 4b. Room temperature, 18 h, 75% yield, pale yellow
powder, mp 229–232 ꢀC. 1H NMR (400 MHz, DMSO-d6): 6.65 (br s,
2H) 6.89 (br s, 1H) 7.34–7.39 (m, 1H) 7.36 (br s, 1H) 7.39–7.46 (m,
2H) 7.64 (d, J¼2.7 Hz, 1H) 7.65–7.69 (m, 2H) 8.35 (s, 1H) 11.27 (br s,
1H); 13C NMR (125 MHz, DMSO-d6): 100.5, 115.3, 118.2, 127.0, 127.7
(2C), 128.0, 128.9 (2C), 131.7, 136.1, 153.7, 159.8, 161.8, 166.3; IR 1437,
1455, 1537, 1549, 1600, 1650, 3190, 3309, 3407 nmax cmꢁ1; LCMS
(ESI) m/z 358 (MþH)þ; HRMS (ESI) calcd for C15H12BrN5OþHþ
358.0298, found 358.0302.
280.1193, found 280.1189.
4.2.2. Ethyl 5-(2-amino-5-chloro-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 3a. To ester 1a (31 mg, 0.1 mmol) in dry DMF
(0.5 mL), under argon atmosphere, N-chlorosuccinimide (13 mg,
0.1 mmol) was added and the mixture was stirred at 80 ꢀC for 2 h.
The reaction mixture was poured into stirred water, the pre-
cipitate was filtered, washed thoroughly and dried, yielding the
title compound (20 mg, 58%) as an off white solid, mp
171–172 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.18 (t, J¼7.1 Hz, 3H) 4.14
4.2.7. 5-(2-Amino-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-pyrrole-3-
carboxamide 5b. Room temperature, 4 h, 72% yield, pale yellow
powder, mp 244 ꢀC. 1H NMR (400 MHz, DMSO-d6): 6.49 (br s, 2H)
7.30 (d, J¼5.2 Hz, 1H) 7.33 (t, J¼7.4 Hz, 1H) 7.37 (br s, 1H) 7.42 (t,
J¼7.6 Hz, 2H) 7.54 (s, 1H) 7.64 (dd, J¼8.4, 1.2 Hz, 2H) 8.30 (d,
J¼5.2 Hz, 1H) 11.70 (s, 1H); 13C NMR (125 MHz, DMSO-d6): 66.3,
106.2, 126.2, 126.8 (2C), 127.5, 128.2 (2C), 129.6, 130.7, 132.2, 157.8,
158.2, 163.4, 167.9; IR 1451, 1556, 1570, 1617, 1658, 3174, 3366, 3415
nmax cmꢁ1; LCMS (ESI) m/z 406 (MþH)þ; HRMS (ESI) calcd for
C15H12IN5OþHþ 406.0159, found 406.0143.
(q, J¼7.1 Hz, 2H) 6.65 (br s, 2H) 7.39–7.48 (m, 3H) 7.55 (d, J¼2.7 Hz,
1H) 7.59–7.66 (m, 2H) 8.30 (s, 1H) 11.70 (br s, 1H); 13C NMR
(125 MHz, DMSO-d6): 13.8, 59.2, 112.5, 113.2, 116.7, 116.9, 126.6,
127.5, 128.4 (2C), 129.7 (2C),139.3, 151.6, 158.5, 161.5, 163.6; IR 1456,
1484, 1543, 1560, 1633, 1646, 1702, 3162, 3297, 3419 nmax cmꢁ1
;
LCMS (ESI) m/z 343 (MþH)þ; HRMS (ESI) calcd for
C17H15ClN4O2þHþ 343.0956, found 343.0968.
4.2.3. Ethyl 5-(2-amino-5-bromo-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 4a. To ester 1a (31 mg, 0.1 mmol) in dry DMF
(0.5 mL), under argon atmosphere, N-bromosuccinimide (18 mg,
0.1 mmol) was added and the mixture was stirred at room tem-
perature for 1 h. The reaction mixture was poured into stirred
water, the precipitate was filtered, washed thoroughly and dried.
The title compound was obtained (25 mg, 65%) as a white solid, mp
169 ꢀC.
4.2.8. Ethyl 5-(2-amino-5-iodo-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 6a. Ester 1a (308 mg, 1 mmol) and iodine
(279 mg, 1.1 mmol) in dry DMF (2 mL), under a nitrogen atmo-
sphere, stirred at –40 ꢀC were treated dropwise with silver tri-
fluoroacetate (243 mg, 1.1 mmol) in DMF (4 mL). The mixture was
stirred at ꢁ40 ꢀC for 6 h and then filtered. The filtrate was diluted
with EtOAc (150 mL), washed with 10% Na2S2O3, dried over sodium
sulfate, evaporated and purified by flash chromatography over sil-
ica gel (DCM/MeOH 95:5) to give the title compound (220 mg, 50%)
as a pale yellow solid, mp 156 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.18 (t, J¼7.1 Hz, 3H) 4.14
(q, J¼7.1 Hz, 2H) 6.67 (br s, 2H) 7.39–7.48 (m, 3H) 7.59–7.64 (m, 2H)
7.66 (d, J¼2.7 Hz, 1H) 8.38 (s, 1H) 11.69 (br s, 1H); 13C NMR
(125 MHz, DMSO-d6): 13.8, 58.8, 101.0, 113.0, 116.1, 116.3, 127.3 (2C),
127.7, 128.1, 129.3 (2C), 139.4, 153.2, 160.4, 161.9, 163.4; IR 1457,
1481, 1540, 1556, 1635, 1712, 3145, 3293, 3427 nmax cmꢁ1; LCMS
(ESI) m/z 387 (MþH)þ; HRMS (ESI) calcd for C17H15BrN4O2þHþ
387.0451, found 387.0457.
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.18 (t, J¼7.1 Hz, 3H) 4.14
(q, J¼7.1 Hz, 2H) 6.65 (br s, 2H) 7.38–7.48 (m, 3H) 7.60–7.66 (m, 2H)
7.77 (d, 1H) 8.52 (s, 1H) 11.65 (br s, 1H); 13C NMR (125 MHz, DMSO-
d6): 13.9, 60.0, 71.2, 113.1, 118.0, 127.7 (3C), 128.7 (2C), 128.8, 130.9,
135.5, 156.3, 161.9, 163.3, 166.6; IR 1456, 1480, 1532, 1548, 1636,
1670, 1711, 3158, 3288, 3423 nmax cmꢁ1; LCMS (ESI) m/z 435
(MþH)þ; HRMS (ESI) calcd for C17H15IN4O2þHþ 435.0313, found
435.0319.
4.2.4. Ethyl 5-(2-amino-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-pyr-
role-3-carboxylate 5a. To ester 1a (31 mg, 0.1 mmol) in dry DMF
(0.5 mL), under argon atmosphere, N-iodosuccinimide (18 mg,
0.08 mmol) was added and the mixture was stirred at room tem-
perature overnight. The reaction mixture was poured into stirred
water, the precipitate was filtered, washed thoroughly and dried.
4.2.9. 5-(2-Amino-5-iodo-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-
carboxamide 6b. Amide 1b (279 mg, 1 mmol) and iodine (267 mg,

10422
E. Vanotti et al. / Tetrahedron 65 (2009) 10418–10423
1.05 mmol) in dry DMF (2 mL), under a nitrogen atmosphere, stir-
red at ꢁ40 ꢀC (internal temperature) were treated dropwise with
silver trifluoroacetate (232 mg, 1.05 mmol) in DMF (3 mL). The
mixture was stirred at ꢁ40 ꢀC for 24 h and then filtered over a short
plug of Celite. The panel was washed with a small amount of DMF
and the filtrate was collected in a flask containing 10% aqueous
Na2S2O3 (25 mL). Precipitation of a pale yellow solid occurred. The
solid was filtered and washed with water. By HPLC-MS analysis the
crude resulted a mixture of starting material (34%), 5b (28%) and
title compound (38%). Purification by flash chromatography over
silica gel (DCM/MeOH 9:1) furnished the title compound (60 mg,
15%) as a pale yellow solid, mp 244 ꢀC.
DMSO-d6): 67.0, 105.9, 122.8, 126.3 (2C), 127.3, 128.3 (2C), 130.4,
131.0, 131.9, 158.2, 160.0, 162.0, 167.9; IR 1446, 1463, 1539, 1557,
1592, 1634, 3178, 3313, 3399 nmax cmꢁ1; LCMS (ESI) m/z 484
(MþH)þ; HRMS (ESI) calcd for C15H11BrIN5OþHþ 483.9264, found
483.9260.
4.2.12. 5-(2-Amino-5-bromo-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-
pyrrole-3-carboxamide 10b. To amide 5b (120 mg, 0.3 mmol) in
DMF (1.5 mL), N-bromosuccinimide (60 mg, 0.34 mmol) was added
and the mixture was stirred at room temperature for 15 h. The
reaction mixture was poured into stirred water, the precipitate was
filtered, washed thoroughly and dried. The title compound was
obtained (120 mg, 83%) as a whitish solid, mp 277 ꢀC.
1H NMR (500 MHz, DMSO-d6)
d ppm 6.66 (br s, 2H) 6.93 (br s,
1H) 7.32 (br s, 1H) 7.34–7.39 (m, 1H) 7.39–7.45 (m, 2H) 7.67 (s, 1H)
7.63–7.69 (m, 2H) 8.51 (s, 1H) 11.30 (br s, 1H); 13C NMR (125 MHz,
DMSO-d6): 71.8, 114.7, 118.0, 127.7 (3C), 128.7 (2C), 128.8, 131.3,
135.6, 156.3, 161.9, 166.3, 166.6; IR 1441, 1454, 1531, 1546, 1569,
1602, 1646, 3166, 3346, 3472 nmax cmꢁ1; LCMS (ESI) m/z 406
(MþH)þ; HRMS (ESI) calcd for C15H12IN5OþHþ 406.0160, found
406.0170.
4.2.13. 5-(2-Amino-5-bromo-pyrimidin-4-yl)-4-bromo-2-phenyl-
1H-pyrrole-3-carboxamide 11b. To amide 1b (140 mg, 0.5 mmol) in
DMF (1.5 mL), N-bromosuccinimide (180 mg, 1 mmol) was added
and the mixture was stirred at room temperature for 15 h. The
reaction mixture was poured into stirred water, the precipitate was
filtered, washed thoroughly and dried. The title compound was
obtained (197 mg, 90%) as a yellowish solid, mp 254 ꢀC.
4.2.10. 5-(2-Amino-pyrimidin-4-yl)-4-chloro-2-phenyl-1H-pyrrole-
3-carboxamide 9b. 4.2.10.1. Step 1. A solution of amide 1b (850 mg,
3 mmol), (Boc)2O (1.7 g, 8 mmol) and DMAP (50 mg, 0.41 mmol) in
THF (20 mL) and DMF (1 mL) was stirred at room temperature for
48 h. The mixture was poured into water and the precipitate was
filtered. It was dissolved in ethyl acetate, washed with water, dried
(anhydrous Na2SO4) and concentrated. The residue, composed by
a mixture of mono-, di- and tri-Boc derivatives, was purified by
flash chromatography (EtOAc/n-hexane 9:1) affording the di-Boc
derivative 7b (14%). LCMS (ESI) m/z 480 (MþHþ).
1H NMR (400 MHz, DMSO-d6): 6.96 (s, 2H) 7.28–7.34 (m, 1H)
7.35 (br s, 1H) 7.41 (t, J¼7.6 Hz, 2H) 7.48 (br s, 1H) 7.56–7.63 (m, 2H)
8.46 (s,1H) 12.01 (s,1H); 13C NMR (125 MHz, DMSO-d6): 96.6,105.6,
119.4, 126.5, 126.7 (2C), 127.3, 128.3 (2C), 130.4, 130.7, 156.6, 160.3,
161.9, 166.3; IR 1459, 1539, 1556, 1594, 1625, 3174, 3321, 3399 nmax
cmꢁ1
;
LCMS (ESI) m/z 436 (MþH)þ; HRMS (ESI) calcd for
C15H11Br2N5OþHþ 435.9403, found 435.9396.
With
a similar procedure the following compound was
obtained.
4.2.14. 5-(2-Amino-5-iodo-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-
4.2.10.2. Step 2. A solution of amide 7b (165 mg, 0.34 mmol)
and N-chlorosuccinimide (46 mg, 0.34 mmol) in DMF (1 mL) was
stirred at 100 ꢀC for 2 h. After cooling the mixture was poured into
stirred water, extracted with ethyl acetate, washed with water,
dried over anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography (EtOAc/n-hexane 5:1) affording
8b (45%). LCMS (ESI) m/z 514 (MþHþ).
pyrrole-3-carboxamide 12b. 55 ꢀC, 8 h, 46% yield, white powder, mp
244 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d ppm 6.90 (s, 2H) 7.25–7.32
(m, 1H) 7.29 (br s, 1H) 7.34 (br s, 1H) 7.40 (t, J¼7.7 Hz, 2H) 7.58 (dd,
J¼8.4, 1.2 Hz, 2H) 8.56 (s, 1H) 11.95 (s, 1H); 13C NMR (125 MHz,
DMSO-d6): 65.6, 79.0,122.9,126.4 (2C),126.7,128.3(2C),130.3,131.1,
133.0, 161.8, 162.3, 165.3, 167.5; IR 1437, 1460, 1533, 1550, 1593,
1634, 3178, 3309, 3395 nmax cmꢁ1; LCMS (ESI) m/z 532 (MþH)þ;
HRMS (ESI) calcd for C15H11I2N5OþHþ 531.9126, found 531.9113.
4.2.10.3. Step 3. To a solution of 8b (80 mg, 0.15 mmol) in MeOH
(1 mL), 4 N HCl in dioxane (3 mL) was added and the mixture was
stirred at room temperature for 20 h and then at 50 ꢀC for 1 h. After
concentration diethyl ether was added under stirring and the
mixture stirred for 30 min. The precipitate was filtered, washed
with diethyl ether and dried and the title compound was obtained
(38 mg, 82%) as a pale yellow powder, mp 252 ꢀC.
Acknowledgements
We thank Daniela Borghi, Nicoletta Colombo, Maristella
Colombo for NMR and mass determinations.
1H NMR (400 MHz, DMSO-d6)
d ppm 6.47 (br s, 2H) 7.16 (d,
References and notes
J¼5.2 Hz, 1H) 7.31–7.38 (m, 1H) 7.38–7.46 (m, 2H) 7.42 (br s, 1H)
7.60 (br s, 1H) 7.61–7.69 (m, 2H) 8.29 (d, J¼5.4 Hz, 1H) 11.64 (br s,
1H); 13C NMR (125 MHz, DMSO-d6): 105.5, 111.2, 119.4, 124.3, 127.0
(2C), 127.5, 128.0 (2C), 130.9, 131.3, 155.5, 158.3, 163.0, 165.4; IR
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and the mixture was stirred at 50 ꢀC for 4 h, then overnight at rt.
The reaction mixture was poured into stirred water, the precipitate
was filtered, washed thoroughly and dried. The title compound was
obtained as an orange solid (277 mg, 82%).
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