4-Aminopyrimidine libraries from the Ugi-Smiles reaction of thiouracil

Article abstract of DOI:10.1016/j.tet.2018.04.058

The Ugi-Smiles reaction of S-benzyl thiouracil have been exploited in several three-step sequences for the preparation of aminopyrimidine libraries with high diversity. After the 4-component coupling, oxidation of the thioether to sulfone is followed by displacement of the latter by various carbon-centered nucleophiles (cyanide, malonate, boronic acids) or amines. The efficiency of the whole sequence was further demonstrated with one-pot procedures.

Full text of DOI:10.1016/j.tet.2018.04.058

Accepted Manuscript
4-Aminopyrimidine libraries from the Ugi-Smiles reaction of thiouracil
Madjid Ait Sidhoum, Laurent El Kaïm, Laurence Grimaud
PII:
S0040-4020(18)30447-2
10.1016/j.tet.2018.04.058
TET 29473
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 February 2018
Revised Date: 12 April 2018
Accepted Date: 17 April 2018
Please cite this article as: Sidhoum MA, El Kaïm L, Grimaud L, 4-Aminopyrimidine libraries from the Ugi-
Smiles reaction of thiouracil, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.058.
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4-Aminopyrimidine Libraries from the Ugi-
Smiles Reaction of Thiouracil
Leave this area blank for abstract info.
Madjid Ait Sidhouma, Laurent El Kaïma and Laurence Grimaud b
aLaboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech-UMR 7652, Université
Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France
bPASTEUR, Département de chimie, École normale supérieure, PSL University, Sorbonne Université, CNRS,
75005 Paris, France

1
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Tetrahedron
journal homepage: www.elsevier.com
4-Aminopyrimidine Libraries from the Ugi-Smiles Reaction of Thiouracil.
Madjid Ait Sidhouma , Laurent El Kaïma Laurence Grimaudb
aLaboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech-UMR 7652, Université Paris-Saclay, 828 Bd des Maréchaux, 91128
Palaiseau, France
b PASTEUR, Département de chimie, École normale supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Ugi-Smiles reaction of S-benzyl thiouracil have been exploited in several three-step
sequences for the preparation of aminopyrimidine libraries with high diversity. After the 4-
component coupling, oxidation of the thioether to sulfone is followed by displacement of the
latter by various carbon-centered nucleophiles (cyanide, malonate, boronic acids) or amines. The
efficiency of the whole sequence was further demonstrated with one-pot procedures.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Ugi-Smiles
pyrimidines
sulfone
Suzuki reaction
with extensions of the strategy to more diverse pyrimidines using
carbon-based nucleophiles (Scheme 1, path b).
1. Introduction
Scheme 1. Aminopyrimidine libraries from S-benzyl thiouracil.
A few years ago, we reported a convenient access to 2,4-
diaminopyrimidine derivatives using a Ugi-Smiles reaction of
thiouracil derivatives (Scheme 1).1 Pyrimidine derivatives are
among the most important heterocyclic scaffolds displaying
various biological activities.2 Aminopyrimidines are widely
represented among these in relation with their use for the
synthesis of the backbone of both DNA and RNA bases (eg
cytosine, adenine..) leading in particular to an impressive number
of applications as anticancer agents.3 The Ugi-Smiles coupling is
a four-component reaction between isocyanides, aldehydes,
primary amines and electron-poor phenols that is perfectly suited
for the conversion of hydroxy and thio substituted six-membered
nitrogen-based heterocycles into libraries of amino heterocycles.4
Besides its interest for the preparation of libraries of DNA
inhibitors, uracil appeared as a particularly attractive target for a
Ugi-Smiles approach due to the selectivity issue brought by the
two hydroxyl groups and the high diversity displayed by
potential reactions at the two sites. After initial deceiving results
obtained with both uracil and thiouracil, Ugi-Smiles couplings
with masked-thiol substrates were successfully settled. The
potential of the resulting adducts to behave as a platform for the
preparation of pyrimidine-based libraries was demonstrated by a
short sequence leading to diaminopyrimidines (Scheme 1, path
R4
R4
N
OH
N
R5
R5
path a
R4CHO
+
CONHR3
SBn
R2
R1
N
N
CONHR3
N
N
N
1) oxidation
R2
R1
R2
R1
X = SBn
N
2) R6NH2
Ugi-Smiles
X
NHR6
R5NH2
R3NC
R4
N
R5
N
X = OH, SH
complex mixture
path b
1) oxidation
CONHR3
R2
2) carbon-based
nucleophiles
R1
N
Nu
Extended aminopyrimidine libraries:
Nu= CN, malonate, Ar
2. Results and discussion
When Ugi-Smiles couplings of uracil with allyl amine,
cyclohexyl isocyanide, and isovaleraldehyde were attempted
under our standard conditions (1 M, 60 °C in methanol or 80 °C
in toluene), we failed to differentiate between the OH-2 and the
OH-4 of uracil and intractable mixtures were obtained using
either stoichiometric amounts or two-fold excess of reagents.
Similar results were obtained with thiouracil, which was
expected to display a better selectivity between the hydroxy
group and the thiol functionality. To address these selectivity
issues, we decided to protect one of the two functional groups
a). We now wish to give a full account on this project together
———
Laurent El Kaim. Tel.: +33-1-8187 2020; e-mail: laurent.elkaim@ensta-paristech.fr
Laurence Grimaud. Tel.: +33-1-44323872; e-mail: laurence.grimaud@ens.fr

2
Tetrahedron
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and selected thiouracil to pursue the study due to a possible S-
certainly the best reagent in terms of side-product formation,
selective alkylation. Thus, the latter was treated in EtOH at 50°C
with benzyl bromide and 3-fluorobenzyl bromide in the presence
of a stochiometric amount of sodium hydroxide to give after 3
hours pyrimidines 1a and 1b in 75% and 72% yields
respectively. The Ugi-Smiles coupling with both protected
thiouracils turned out to be rather efficient when performed in
MeOH as shown by the various aminopyrimidines 2 prepared
from a set of amines, aldehydes and isocyanides (Table 1).
Aliphatic and aromatic aldehydes could be used with similar
yields together with cyclohexyl or 4-benzyl isocyanides (Table 1,
entries 1-3, 7-12). Isocyanoesters gave slightly lower yields in
agreement with their reduced nucleophilicity (Table 1, entries 10-
12).
however, its use generally requires a further optimization due
to the need of a metal catalyst.6 Thus, m-CPBA was selected
for its broad scope and simple use.7 The oxidation step was
optimized using the thioether 2g as substrate with three
equivalents of m-CPBA by varying the solvent of the reaction
-using methanol, toluene or dichloromethane. The latter gave
the best results in terms of yields and reaction time: 95%
isolated yield within 30 minutes at rt compared to 90% over 5
hours in methanol and 70% for 6 hours in toluene. With these
conditions in hand, a set of various Ugi-Smiles adducts were
efficiently oxidized leading to sulfones 3 as presented in
Table 2.
Table 2. Oxidation of Ugi-Smiles adducts
Table 1. Ugi-Smiles coupling of S-benzyl thiouracil
R2
R3
R4
Yield
87%
94%
89%
88%
82%
88%
95%
85%
85%
2
Entry
3
R1
R2
R3NH2
R4NC
Yield
1
2
3
4
5
6
7
8
9
Entry
1
Product
2a
2b
2c
2d
i-Bu
i-Bu
H
allyl
allyl
allyl
p-ClBn
Cy
3a
3b
3c
3d
91%
86%
72%
71%
82%
88%
72%
85%
85%
45%
47%
51%
72%
85%
77%
87%
98%
53%
NH2
2a
2b
2c
2d
2e
2f
H
H
i-Bu
i-Bu
p-ClBnNC
Cy
NH2
NH2
2
CyNC
i-Bu
i-Pr
i-Pr
Ph
Et
p-ClBn
allyl
Cy
Cy
3
H
H
H
H
H
H
H
H
H
H
F
H
i-Bu
i-Pr
i-Pr
Ph
Et
CyNC
CyNC
2e
2f
3e
3f
4
p-ClBnNH2
p-ClBn
allyl
Cy
NH2
5
CyNC
2g
2h
2i
3g
3h
3i
Cy
6
p-ClBnNH2
CyNC
NH2
p-ClBn
allyl
p-ClBn
t-Bu
7
2g
2h
2i
CyNC
Et
8
p-ClBnNH2
p-ClBnNC
t-BuNC
NH2
9
Et
NH2
10
11
12
13
14
15
16
17
18
2j
H
MeOOCCH2NC
MeOOCCH2NC
EtOOCCH2NC
p-ClBnNC
CyNC
The potential of the new sulfones 3 was next evaluated
towards different families of nucleophiles. According to seminal
reports on nucleophilic substitution of heteroaryl sulfones, we
decided to first test the reaction with cyanide8 and malonate
anions.9
MeO
NH2
H
2k
2l
MeO
MeO
NH2
NH2
H
2m
2n
2o
2p
2q
2r
i-Bu
Ph
Ph
i-Bu
i-Pr
Et
NH2
NH2
NH2
F
MeO
Table 3. Cyanation of sulfones 3
F
p-MeOBnNC
CyNC
F
NH2
NH2
F
CyNC
F
t-BuNC
R2
i-Bu
i-Pr
i-Pr
Ph
Et
R3
allyl
R4
Cy
Yield
85%
81%
82%
82%
83%
88%
2
In order to showcase the synthetic potential of this first
reaction, the ability to displace the thioether group by various
nucleophiles was next envisioned. Though the direct
displacement of a thioether moiety tethered at the 2-position
of a nitrogenated heterocycle by carbon-based nucleophiles
has been reported under various metal-catalyzed conditions,5
we decided to first oxidize the thioether to a sulfone and to
treat the latter with several nucleophiles. Even if more
lengthy, we surmised that the proper selection of a good
leaving group would lead to a flexible set of conditions with a
wide scope of nucleophiles.
Entry
3
1
2
3
4
5
6
3b
3e
3f
3g
3h
3i
4b
4e
4f
allyl
Cy
p-ClBn
allyl
Cy
4g
4h
4i
Cy
p-ClBn
allyl
p-ClBn
t-Bu
Et
Using 1.2 equiv of potassium cyanide as nucleophile with
sulfone 3g, best conditions were obtained in DMF as solvent and
by heating the mixture at 50°C for one day. Under these
optimized conditions, the desired cyano pyrimidine 4g was
Various oxidizing agents have been reported for the
conversion of thioethers into sulfones. Hydrogen peroxide is

3
isolated in 82% yields (Table 3, entry 4). Lower temperature
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required increased reaction time and led to lower yields (DMF, rt,
3 days, 50%) whereas less polar solvents such as toluene or
acetonitrile gave poor yields (around 10% within 2 days at
reflux) in agreement with the poor solubility of potassium
cyanide in these solvents. A set of six pyrimido sulfones 3 were
submitted to these experimental conditions to afford cyano
pyrimidines 4 in satisfying yields as displayed in Table 3.
Similarly, addition of malonate were successfully tested. In this
case, DMF could be replaced by acetonitrile as solvent using
cesium carbonate to in situ generate the anion. Pyrimido sulfones
3 were converted into substituted malonates 5 in very good yields
within 2 days (Table 4, entries 1-4).
R1
R2
R3
R4
Yield
75%
70%
72%
60%
69%
74%
70%
73%
75%
65%
61%
63%
77%
81%
Entry
1
3
6a
6b
6c
6d
4-MeC6H4
2-MeC6H4
i-Bu
i-Bu
allyl
allyl
p-ClBn
2
Cy
3
Ph
i-Pr
Ph
allyl
allyl
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
4
4-MeC6H4
2-MeC6H4
4-ClC6H4
5
i-Bu
i-Bu
i-Bu
i-Bu
i-Pr
i-Bu
i-Bu
Ph
p-ClBn
allyl
6e
6f
Table 4. Substitution by dimethyl malonate
6
7
6g
6h
6i
3,4-Cl2C6H3
4-FC6H4
allyl
8
allyl
9
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-MeCOC6H4
4-EtC6H4
allyl
10
11
12
13
14
6j
allyl
6k
6l
p-ClBn
allyl
R2
R3
R4
Yield
86%
87%
91%
83%
3
Entry
5
1
2
3
5
3a
3b
3c
5a
5b
5c
i-Bu
i-Bu
allyl
allyl
p-ClBn
6m
6n
i-Pr
i-Pr
p-ClBn
p-ClBn
Cy
4-t-BuC6H4
H
allyl
allyl
Cy
Cy
3e
i-Pr
5e
We next examined the behavior of amines as nucleophiles. There
are many examples concerning the displacement of sulfonyl
groups tethered to nitrogen-based heterocycles by amines.11
These reactions are usually performed in protic solvents such as
ethanol whereas the oxidation step was formerly optimized in
dichloromethane. Moreover, the use of an excess of oxidizing
agent to form the sulfone prevents the development of a one-pot
procedure. Indeed, amines are known to be readily oxidized to
hydroxylamine by m-CPBA. Thus, direct addition of amines into
the crude mixture after oxidation requires either prior destruction
of the remaining oxidant or the use of a large excess of the
amine. The latter solution was preferred together with the choice
of relatively non-expensive amines. First attempts towards one-
pot oxidation/amine addition starting from the Ugi-Smiles adduct
2n and 3 equiv of morpholine with dichloromethane as sole
solvent for both steps were rather deceiving as the expected
diamino pyrimidine 7a was obtained in a moderate 38% yield
after 24 hours reflux. Controlled experiments demonstrated a
very efficient oxidation followed by a sluggish second step in
dichloromethane. When the same reaction was performed on
isolated sulfone in refluxing toluene, the diaminopyrimidine
could be isolated up to 80% yield. A 1:1 mixture of
dichloromethane/toluene was then selected to balance the
efficiency of both steps. The oxidation turned out to be slightly
slower but still high yielding -up to 90% if the reaction mixture is
left two hours at rt before adding the amine. The temperature was
then slowly raised up to the boiling point of toluene while the
dichloromethane distilled out of the mixture. To our delight, after
7 hours of reflux, the expected pyrimidine 7a was isolated in
74% yield directly from 2n (Table 6). Beside morpholine,
primary amines such as 4-chlorobenzyl amine could be
efficiently used in this one-pot process.
Following these additions of stabilized carbanions, we decided
to examine whether more diversity could be achieved under
transition metal-catalyzed reactions. Though few examples
reported, we were not able to observe any substitution of the
sulfonyl moiety of 3b and 3g by phenylacetylene or 4-methoxy
substituted phenylacetylene under standard Sonogashira
conditions (PdCl2(PPh3)2, CuI, NEt3 in DMF, CH3CN, THF or
NEt3 as solvents). We next examined the possible substitution of
the sulfonyl group according to a Suzuki-type reaction. The
direct coupling of thioether with boronic acids has attracted much
attention with the disclosure of efficient Pd/Cu co-catalyzed
conditions to trigger the Liebeskind-Srogl coupling. The latter
was also described for heterocyclic derivatives.10 In contrast,
there are only few examples of cross-coupling reactions between
heteroaryl alkylsulfones and boronic acids. For instance, Liu and
Robins have reported a Pd/NHC catalytic system to perform an
efficient Suzuki reaction of a sulfonyl purine derivative.11
Gratifyingly, when the sulfone 3a was treated with 1.5 equiv of
phenylboronic acid together with 5 mol% of Pd(OAc)2 and 15
mol% of PPh3 in refluxing toluene under argon, the formation of
the desired arylamino pyrimidine 6a was achieved in 75% yields.
These simple conditions were not optimized further and a small
library of fourteen aminoaryl pyrimidines was synthesized
according to this procedure. Good yields were obtained using
either electron-rich or electron-poor arylboronic acids as
displayed in Table 5.
Table 5. Suzuki-type reaction of sulfones 3

4
Tetrahedron
Table 6. One-pot diaminopyrimidine formation
Scheme 2. One-pot three-step diaminopyrimidine synthesis from
ACCEPTED MANUSCRIPT
S-benzyl thiouracil.
Entry
1
2
2n
R5R6NH
Product
Yield
74%
2
3
2n
2n
57%
3. Conclusion
To conclude, we have disclosed a three-step procedure
towards libraries of aminopyrimidine scaffolds, which are of
important biological interest. The sequence displays as a key-step
the Ugi-Smiles coupling of S-benzyl thiouracil. The thioether
group is then exploited to raise the diversity of the whole
transformation through substitution by various nucleophiles. The
overall sequence showcases the synthetic potential of Ugi-Smiles
couplings for the preparation of pyrimidine bases.
68%
4
5
2q
2q
74%
60%
4. Experimental Part
4.1. General
NMR spectra were recorded at 298 K using a Bruker
1
AVANCE 400 spectrometer. H NMR spectra were recorded at
400 MHz and residual solvent peaks were used as an internal
reference (CDCl3 δ 7.26). Data are reported as follows: chemical
shift in ppm, apparent multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, p = pentet, m = multiplet or overlap of
nonequivalent resonances), coupling constants, integration. 13C
NMR spectra were recorded at 100 MHz and deuterated solvent
peaks were used as an internal reference (CDCl3 δ 77.16). Data
are reported as follows: chemical shift in ppm, multiplicity
deduced from DEPT experiments (CH3, CH2, CH, Cq), apparent
multiplicity, coupling constants and integration where relevant.
Analytical TLC was performed with Merck silica gel plates, pre-
coated with silica gel 60 F254 (0.2 mm). Flash chromatography
employed VWR (230–400 mesh) silica gel. Reactions were
conducted under a positive pressure of dry nitrogen or argon
Solvents were either obtained from commercial sources or dried
6
7
8
2m
2a
51%
81%
73%
2b
with
a MBRAUN Solvent Purification System SPS-800.
Commercially available chemicals were used as purchased. IR
spectra were recorded on a Perkin Elmer Spectrum 65 FT-IR
Spectrometer. High-resolution (HRMS) mass spectra were
Encouraged by this first successful one-pot two-step formation of
diaminopyrimidines, we decided to examine the more
challenging one-pot three-step version of the whole sequence
including the multicomponent reaction. Thanks to the versatile
efficiency of Ugi-Smiles couplings in both protic and aprotic
solvents, methanol was thus replaced by toluene for the first Ugi-
Smiles step. After completion, the mixture was diluted with
dichloromethane followed by sequential addition of m-CPBA and
amine. This sequence afforded 7a, 7b and 7h in respectively 46,
43 and 48% yields (Scheme 2). Even though these results may be
considered as moderate, they demonstrate the robustness of this
three-step sequence with a 80% average yield per step.
performed on a JEOL JMS-Gcmate II, GC/MS system
spectrometer using an electronic impact ionization source. The
preparations and characterizations of 1a, 1b, 2a, 2b, 2c, 2g, 2j,
2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 7a, 7b, 7c, 7d, 7e, 7f, 7g and 7h
were already described previously,1 the general procedures
followed are just presented for these compounds.
4.2. Synthesis of thiouracil derivative 1a and 1b
4.2.1. General procedure
A mixture of thiouracil (15 mmol, 1.92 g), alkylating agent (15
mmol), potassium carbonate (30 mmol, 4.15g) and Triton X-100

5
(0.04 mmol, 25 mg) in water (120 mL) was refluxed for 3 h. The
(100.6 MHZ, CDCl3) δ 169.9, 168.8, 162.0, 155.8, 137.8,
ACCEPTED MANUSCRIPT
aqueous layer was extracted with ethyl acetate (3x100 mL) and
the combined organic extracts were dried over anhydrous
MgSO4. After filtration, the solvent was evaporated under
reduced pressure and the residue was chromatographed on silica
gel. This procedure was followed using benzyl chloride (15
mmol, 1.89 gr) and m-fluorobenzyl chloride (15 mmol, 2.17 gr).
The crude were purified by flash chromatography over silica gel
(EtOAc/PE, 40:60) to afford 1a (2.44 g, 75%) and 1b (2,83 g, 80
%).
135.4, 132.8, 128.7, 128.6, 127.7, 127.3, 127.2 , 101.2, 63.5,
48.1, 47.4, 35.2, 33.0, 32.7, 27.5, 25.5, 24.7, 19.8, 19.2. IR (thin
film): 2933, 1653, 1573, 1471, 1346 cm-1. HRMS Calculated for
C29H35ClN4OS: 522.2220, found: 522.2215.
4.3.2.4:
N-(4-chlorobenzyl)-2-((4-chlorobenzyl)(2-(benzylthio)
pyrimidin-4-yl)amino) butanamide (2h). The product was
obtained as a green oil (350 mg, 64%) after chromatography on
silica gel (Et2O/EP 20:70). Rf (Et2O/EP 50:50). 0.7. H NMR
1
(400 MHZ , CDCl3) δ 8.01 (d, 1H, J = 6.1 Hz), 7.44 (d, 2H, J =
7.3 Hz), 7.35 (d, 2H, J = 7.3 Hz), 7.30-7.23 (m, 5H), 7.12-7.05
(m, 4H), 6.57 (br s, 1H), 6.00 (d, 1H, J = 6.1 Hz), 5.16 (br s, 1H),
4.75 (d, 1H, J = 17.4 Hz), 4.65-4.48 (m, 1H), 4.41-4.33 (m, 2H),
4.33-4.23 (m, 2H), 2.15-2.03 (m, 1H), 1.73-1.61 (m, 1H), 0.93 (t,
3H, J = 7.3 Hz). 13C NMR (100.6 MHZ, CDCl3) δ 170.3, 161.8,
156.1, 137.7, 136.5, 135.6, 133.2, 133.1, 129.0, 128.9, 128.8,
128.7, 127.5, 127.3, 100.9, 59.1, 48.1, 42.7, 35.2, 22.1, 11.1. IR
(thin film): 2974, 1573, 1534, 1471, 1346 cm-1. HRMS
Calculated for C29H28C12N4OS: 550.1361, found: 550.1371.
4.3. Synthesis of Ugi adducts 2
4.3.1. General procedure
To a 1 M solution of the aldehyde (1.0 mmol) in methanol was
added successively 1.0 equiv of amine, 1.0 equiv of isocyanide,
and 1.0 equiv of pyrimidine 1a or 1b under inert atmosphere.
The resulting mixture was stirred until completion (TLC). It was
then concentrated in vacuo, and the crude product was purified
by flash chromatography on silica gel.
4.3.2.5:
2-(allyl(2-(benzylthio)pyrimidin-4-yl)amino)-N-tert-
4.3.2.1: 2-((4-chlorobenzyl)(2-(benzylthio)pyrimidin-4-yl)amino)-
N-cyclohexyl-4-methylpentanamide (2d). The product was
obtained as an oil (380 mg, 71%) after chromatography on silica
butylbutanamide (2i). The product was obtained as a yellow solid
(210 mg, 54%) after chromatography on silica gel (Et2O/EP
30:70). MP = 93-94 °C. Rf (Et2O/EP 30:70) 0.2. H NMR (400
1
1
gel (AcOEt/EP 60:40). Rf (AcOEt/EP 70: 30) 0.3. H NMR
MHZ, CDCl3) δ 8.08 (d, 1H, J = 6.1 HZ), 7.46 (d, 2H, J = 7.6 HZ),
7.37-7.31 (m, 2H), 7.27 (t, 1H, J = 7.1 HZ), 6.25 (br s, 1H), 6.20
(d, 1H, J = 6.1 HZ), 5.85-5.74 (m, 1H), 5.23 (d, 1H, J = 9.1 HZ),
5.20 (d, 1H, J = 15.7 HZ), 5.08-4.87 (br s, 1H), 4.41 (s, 2H), 4.09
(dd, 1H, J = 17.4, 5.1 HZ), 3.94 (br d, 1H, J = 17.4 HZ), 1.73-1.65
(m, 2H), 1.30 (s, 9H), 0.89 (t, 3H, J = 7.3 HZ). 13C NMR (100.6
MHZ, CDCl3) δ 170.0, 169.7, 161.5, 155.6, 137.7, 133.1, 128.8,
128.5, 127.2, 117.4, 100.9, 59.4, 51.1, 47.2, 35.2, 28.7, 21.5,
10.9. IR (thin film): 2972, 1744, 1573; 1367; 1213 cm-1. HRMS
Calculated for C22H30N4OS: 398.2140, found: 398.2140.
(400 MHZ , CDCl3) δ 8.04 (d, 1H, J =6.1 HZ), 7.47 (d, 2H, J =
7.8 HZ), 7.39-7.34 (m, 2H), 7.33-7.29 (m, 3H), 7.14 (d, 2H, J =
7.8 HZ), 6.21 (br s, 1H), 6.00 (d, 1H, J = 6.1 HZ), 5.33-5.28 (m,
1H), 4.67 (s, 2H), 4.45 (s, 2H), 3.74-3.62 (m, 1H), 1.99-1.91 (m,
1H), 1.88-1.82 (m, 1H), 1.73-1.66 (m, 2H), 1.64-1.48 (m, 4H),
1.39-1.29 (m, 2H), 1.24-1.10 (m, 2H), 1.06-0.97 (m, 1H), 0.93 (d,
3H, J = 6.6 HZ), 0.90 (d, 3H, J = 6.6 HZ). 13C NMR (100 MHZ ,
CDCl3) δ 170.3, 169.4, 161.7, 156.0, 137.6, 135.7, 133.1, 129.0,
128.9, 128.6, 127.7, 127.3, 101.1, 56.1, 48.2, 48.0, 37.4, 35.2,
32.8, 32.7, 25.5, 25.3, 24.6, 22.8, 22.7. IR (thin film): 2933,
1740, 1589, 1471, 1342 cm-1. HRMS Calculated for
C30H37ClN4OS: 536.2377, found: 536.2384.
4.4. Synthesis of sulfone Ugi adducts 3
4.3.2.2:
2-(allyl(2-(benzylthio)pyrimidin-4-yl)amino)-N-cyclo-
4.4.1. General procedure
hexyl-3-methylbutanamide (2e). The product was obtained as a
To a stirred solution Ugi-Smiles adduct 2 (1.0 mmol) in
dichloromethane (15 mL) was added m-CPBA (3.0 equiv, 3.0
mmol) at 0°C. The mixture was then allowed to warm to room
temperature. After 60 min, a saturated aqueous solution of
Na2S2O3 was added to the reaction mixture and the resulting
aqueous layer was extracted 3 times with dichloromethane. The
combined organic phases were washed with a saturated aqueous
solution of sodium bicarbonate, followed by brine, dried over
anhydrous MgS04, filtered and the solvent removed in vacuo. The
product was purified by flash chromatography.
yellow oil (430 mg, 98%) after chromatography on silica gel
(Et2O/EP 30:70). Rf (Et2O/EP 50:50)) 0.5. H NMR (400 MHZ,
1
CDCl3) δ 7.96 (d, 1H, J = 6.1 HZ), 7.38 (d, 2H, J =7.6 HZ), 7.27-
7.22 (m, 2H), 7.21-7.15 (m, 1H), 6.09 (d, 1H, J = 6.1 HZ), 5.92-
5.67 (br s, 1H), 5.65-5.54 (m, 1H), 5.10-5.00 (m, 2H), 4.84-4.49
(br s, 1H), 4.29 (s, 2H), 4.00-3.91 (m, 2H), 3.62-3.51 (m, 1H),
2.36-2.22 (br s, 1H), 1.76 (d, 1H, J = 11.9 HZ), 1.59 (d, 2H, J =
11.9 HZ), 1.53-1.45 (m, 2H), 1.27-1.16 (m, 2H), 1.11-0.98 (m,
3H), 0.87 (d, 3H, J = 6.6 HZ), 0.70 (d, 3H, J = 6.6 HZ). 13C NMR
(100.6 MHZ, CDC13) 169.8, 169.0, 161.8, 155.6, 137.9, 132.9,
128.7, 128.6, 127.2, 117.4, 101.0, 63.0, 47.9, 46.6, 35.2, 32.9,
32.6, 26.8, 25.5, 24.7, 24.6, 19.8, 19.1. IR (thin film): 2933,
1740, 1573, 1367, 1220 cm-1. HRMS Calculated for
C25H34N4OS: 438.2453, found: 438.2446.
4.4.2.1: N-(4-chlorobenzyl)-2-(allyl(2-(benzylsulfonyl)pyrimidin-
4-yl)amino)-4-methylpentanamide
(3a). The product was
obtained as a yellow solid (460 mg, 87%) after chromatography
on silica gel (AcOEt/EP 25:75). MP = 153-154°C. Rf
(AcOEt/EP 50:50) 0.6. 1H NMR (400MHz,CDCl )
1H, J
δ
8.27(d,
= 6.1 Hz), 7.35-7.25 (m, 5H), 7.19 (d, 2H, J = 8.3 HZ),
7.10 (d, 2H, J = 8.3 HZ), 6.52 (d, 1 , J = 6.1 HZ), 5.76-5.65
(m, H), 5.29-5.23 (m, H), 5.22 (d, H, J= 10.6 Z), 5.11 (d, l
H, = 17.4 Z), 4.68 (d, H, = 13.6 H, 13.6
H), 3.95 (br d, lH, J =
), 1.65-1.56 (m, 1 ), 1.55-1.44 (m,
Z), 0.90 (d, 3H, J=6.6
Z). 13C NMR
3
4.3.2.3: 2-((4-chlorobenzyl)(2-(benzylthio)pyrimidin-4-yl)amino)-
N-cyclohexyl-4-methylbutanamide (2f). The product was
obtained as a yellow oil (360 mg, 68%) after chromatography on
H
1
1
1
H
1
J
H
1
J
HZ), 4.61 (d,
1
J =
silica gel (Et2O/EP 50:50). Rf (Et2O/EP 50:50) 0.3. H NMR
H
Z), 4.32-4.18 (m, 2H), 4.17-4.10 (m,
17.7 HZ), 2.00-1.92 (m, 1
H), 0.93 (d, 3H, J=6.6
1
(400 MHZ, CDCl3) δ 7.96 (d, 1H, J = 6.1 HZ), 7.48 (d, 2H, J = 7.6
Hz), 7.36 (t, 2H, J = 7.8 HZ), 7.29-7.26 (m, 1H), 7.24 (d, 2H, J =
7.8 HZ), 7.05 (d, 2H, J = 7.6 HZ), 5.98-5.92 (m, 2H), 4.89 (br d,
1H, J = 16.9 HZ), 4.67-4.48 (m, 2H), 4.45-4.33 (m, 2H), 3.68-
3.57 (m, 1H), 2.50-2.32 (m, 1H), 1.91-1.81 (m, 1H), 1.73-1.65
(m, 3H), 1.63-1.56 (m, 1H), 1.33-1.27 (m, 2H), 1.19-1.11 (m,
3H), 0.98 (d, 3H, J = 6.3 Hz), 0.81 (d, 3H, J = 6.3 Hz). 13C NMR
H
H
H
1
H
(100.6 MHz, CDCl3) δ 170.0, 163.3, 162.2, 155.8, 136.9,
132.8 , 131.9, 131.2, 129.1, 128.9, 128.7, 128.6, 127.0, 117.7,
107.1, 57.4, 56.4, 47.5, 42.6, 37.3, 25.0, 22.8, 22.6. IR (thin

6
Tetrahedron
-1
film): 2958, 1740, 1674, 1489, 1217 cm . HRMS Calculated
163.4, 162.6, 155.6, 132.0, 131.2, 128.8, 128.7, 127.3, 118.3,
ACCEPTED MANUSCRIPT
for C27H31ClN4O3S:526.1805,found:526.1828
.
107.4, 64.5, 57.4, 48.3, 47.3, 32.7, 32.3, 26.8, 25.3, 24.9, 24.8,
19.5,19.2. IR (thin film): 2933, 1737, 1590, 1374, 1217 cm-1.
HRMS Calculated for C25H34N4O3S: 470.2352; found: 470.2331.
4.4.2.1:
hexyl -4-methylpentanamide
yellow oil (450 mg, 94%) after chromatography on silica gel
2-(allyl(2-(benzylsulfonyl)pyrimidin-4-yl)amino)-N-cyclo-
(
3b The product was obtained as a
).
4.4.2.6:
2-((4-chlorobenzyl)(2-(benzylsulfonyl)pyrimidin-4-yl)
3f The product was
1
amino)-N-cyclohexyl-4-methylbutanamide
obtained as a yellow oil (490 mg, 88%) after chromatography on
(
).
(Et2O/EP 35:65). Rf (Et2O/EP 50:50) 0.5. H NMR (400 MHz
CDCl ) δ 8.22 (d, 1H, J 6.1 HZ), 7.29-7.21 (m, 5H), 6.59 (d,
7.6 Hz), 6.44 (d, 1H, J 6.1 HZ), 5.74-5.61 (m, lH),
5.16 (d, 1H, J = 10,4 Hz), 5.12-5.07 (br s, 1H), 5.04 (d, 1H, J
17.7 HZ), 4.74 (d, 1H, J 13.9 HZ), 4.56 (d, 1 H , J 13.9 HZ),
4.20 (d, 1H, J= 17.4HZ), 3.88 (d, 1H, J = 17.4HZ), 3.56-3.50 (m,
1H), 1.90-1.81(m, 1H), 1.75(d, 1H, 10.9 Z), l.64-1.56 (m,
6.3
,
=
3
=
1
silica gel (Et2O/EP 40:60). Rf (Et2O/EP 50:50) 0.3. H NMR
1H, J
=
(400 MHZ, CDCl3) δ 8.24 (d, 1H, J = 6.1 HZ), 7.48-7.33 (m, 5H),
7.31-7.25 (m, 2H), 7.09-6.98 (m, 2H), 6.69 (br s, 1H), 6.31 (d,
1H, J = 6.1 HZ), 4.98-4.94 (m, 3H), 4.72-4.63 (m, 2H), 3.73-3.57
(m, 1H), 2.54-2.37 (m, 1H), 1.92-1.81 (m, 1H), 1.77-1.72 (m,
1H), 1.66-1.55 (m, 3H), 1.33-1.28 (m, 1H), 1.27-1.21 (m, 2H),
1.21-1.18 (m, 1H), 1.01 (d, 3H, J = 6.3 HZ), 0.97-0.92 (m, 1H),
0.79 (d, 3H, J = 6.3 HZ). 13C NMR (100.6 MHZ, CDCl3) δ 168.2,
163.4, 162.8, 155.9, 134.0, 133.2, 131.2, 129.0, 128.9, 128.7,
127.7, 127.2, 107.5, 64.9, 57.4, 48.4, 47.8, 32.8, 32.5, 27.5, 25.3,
24.9, 19.6, 19.3. IR (thin film): 2937, 1740, 1587, 1370, 1213
cm-1. HRMS Calculated for C29H35CIN4O3S: 554.2118, found:
554.2110.
=
=
=
J
=
H
1H), 1.53-l.36 (m, 5H), 1.25-0.95 (m, 5H), 0.84 (d, 3H, J
=
HZ), 0.81 (d, 3H, J =6.3 HZ). 13C NMR (100.6 MHZ, CDCl3) δ
168.7, 163.4, 162.2, 155.7, 132.1, 131.2, 128.8,128.7, 127.1,
117.4, 107.1, 57.3, 56.2, 48.5, 47.3, 37.1, 32.7, 32.3, 25.3, 25.1,
24.9, 22.9, 22.7. IR (thin film): 2933, 1635, 1587, 1489, 1119
cm-1. HRMS Calculated for C26H36N4O3S: 484.2508, found:
484.2484.
4.4.2.3:
hexylacetamide
2-(allyl(2-(benzylsulfonyl)pyrimidin-4-yl)amino)-N-cyclo-
3c The product was obtained as an oil (380 mg,
4.4.2.7: 2-(allyl(2-benzylsulfonyl)pyrimidin-4-yl)amino)-N-
cyclohexyl-2-phenylacetamide (3g). The product was obtained
(
).
89%) after chromatography on silica gel (Et2O/EP 30:70). Rf
(Et2O/EP 50:50) 0.6. H NMR (400 MHZ, CDCl3) δ 8.23 (d,
as a yellow oil (480 mg, 95%) after chromatography on silica gel
1
1
(Et2O/EP 50:50). Rf (Et2O/EP 50:50) 0.3. H NMR (400 MHZ,
1H,J= 5.8 HZ), 7.30-7.19 (m, 5H), 6.61 (br s, 1H), 6.47 (d, 1H, J
= 5.8 HZ), 5.78-5.67 (m, 1H), 5.18 (d, 1H, J = 10.4 HZ), 5.04 (d,
1H, J= 16.7 HZ), 4.62 (s, 2H), 4.17-4.05 (m, 2H), 3.97 (s, 2H),
3.70-3.45 (m, 1H), 1.69-1.45 (m, 5H), 1.21-1.11 (m, 2H), 1.04-
0.92 (m, 3H). 13C NMR (100.6 MHz, CDC13) δ 167.0, 163.7,
161.7, 156.0, 131.3, 130.2, 128.8, 128.7, 127.1, 117.7, 105.8,
57.3, 52.6, 52.4, 48.7, 32.6, 25.3, 25.0. IR (thin film): 2933,
1740, 1590,1370, 1217 cm-1. HRMS Calculated for
C22H28N4O3S: 428.1882, found: 428.1881
CDCl3) δ 8.32 (d, 1H, J = 6.1 HZ), 7.41-7.33 (m, 10H), 6.62 (d,
1H, J = 6.1 HZ), 6.44 (br s, lH),6.30 (d, 1H, J = 7.8 HZ), 5.56-
5.44 (m, 1H), 5.06 (d, 1H, J = 10.8 HZ), 5.02 (d, 1H, J = 18.7
HZ), 4.70 (s, 2H), 4.15 (dd, 1H, J =15.2, 7.1 HZ), 4.10-4.00 (m,
1H), 3.82-3.72 (m, 1H), 1.92 (d, 1H, J = 11.5 HZ), 1.80 (d, 1H, J
= 11.5 HZ), 1.72-1.63 (m, 2H), 1.63-1.55 (m, 1H), 1.31-1.26 (m,
2H), 1.15-1.05 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 168.4,
163.6, 162.3, 155.7, 134.5, 132.3, 131.3, 129.7, 128.9, 128.8,
128.7, 127.1, 117.4, 107.1, 62.4, 57.5, 49.1, 48.9, 32.8, 32.5,
25.4, 24.9, 24.8. IR (thin film): 2937, 1740, 1587, 1489, 1220
cm-1. HRMS Calculated for C28H32N4O3S: 504.2195, found:
504.2218.
4.4.2.4:
yl)amino)-N-cyclohexyl-4-methylpentanamide
was obtained as yellow oil (500 mg, 88%) after
2-((4-chlorobenzyl)(2-(benzylsulfonyl)pyrimidin-4-
(
3d The product
).
a
chromatography on silica gel (AcOEt/EP 70:30). Rf (AcOEt/EP
70:30) 0.3. H NMR (400 MHZ, CDCl3) δ 8.17 (d, 1H, J = 6.1
4.4.2.8:
N-(4-chlorobenzyl)-2-((4-chlorobenzyl)(2-
3h The
1
(benzylsulfonyl)pyrimidin-4-yl)amino)butanamide
(
).
HZ), 7.35 (d, 2H, J = 7.3 HZ), 7.28-7.21 (m, 5H), 6.95 (d, 2H, J =
7.3 HZ), 6.67 (br s, 1H), 6.20 (d, 1H, J = 6.1 HZ), 5.12 (br s, 1H),
4.88-4.76 (m, 2H), 4.57 (d, 1H, J = 13.9 HZ), 4.48 (d, 1H, J =
16.9 HZ), 3.57-3.44 (m, 1H), 1.94-1.87 (m, 1H), 1.83-1.72 (m,
1H), 1.64-1.56 (m, 1H), 1.52- 1.38 (m, 4H), 1.37-1.28 (m, 1H),
1.23-1.02 (m, 4H), 0.86-0.84 (m, 1H), 0.81 (d, 3H, J = 6.3 HZ),
0.79 (d, 3H, J = 6.3 HZ). 13C NMR (100.6 MHz, CDCl3) δ 168.8,
163.4, 162.5, 156.1, 134.5, 133.5, 131.3, 129.2, 128.9, 128.7,
128.3, 127.1, 107.1, 57.3, 56.7, 48.7, 48.1, 37.5, 32.7, 32.3, 25.5,
25.4, 25.3, 24.9, 23.0, 22.6. IR (thin film): 2933, 1656, 1590,
1492, 1321 cm-1. HRMS Calculated for C30H37CIN4O3S:
568.2275, found: 568.2278.
product was obtained as a yellow oil (500 mg, 85%) after
chromatography on silica gel (Et2O/EP 20:80). Rf (Et2O/EP
1
50:50) 0.7. H NMR (400 MHZ, CDCl3) δ 8.29 (d, 1H, J = 6.1
Hz), 7.48-7.44 (m, 1H), 7.38-7.36 (m, 4H), 7.33-7.32 (m, 1H),
7.31-7.29 (m, 1H), 7.25- 7.23 (m, 1H), 7.22-7.20 (m, 1H), 7.11
(d, 2H, J = 8.3 HZ), 7.05 (d, 2H, J = 8.3 HZ), 6.35 (d, 1H, J = 6.1
HZ), 5.01-4.89 (m, 2H), 4.80-4.74 (m, 1H), 4.70-4.64 (m, 1H),
5.57-4.48 (m, 1H), 4.36 (dd, 1H, J = 14.7, 6.1 HZ), 4.11 (dd, 1H,
J = 14.7, 6.1 HZ), 2.14-2.07 (m, 1H), 1.66-1.58 (m, 1H), 0.90 (t,
3H, J =7.3 HZ). 13C NMR (100.6 MHZ, CDC13) δ 169.7, 163.3,
162.5, 156.3, 136.8, 134.5, 133.5, 133.0, 131.3, 129.3, 129.2,
129.0, 128,8, 128.6, 127.1, 107.0, 60.1, 57.3, 48.4, 42.7, 22.1,
10.7. IR (thin film): 2940, 1740, 1594, 1370, 1217 cm-1. HRMS
Calculated for C29H28Cl2N4O3S: 582.1259, found: 582.1277.
4.4.2.5:
2-(allyl(2-(benzylsulfonyl)pyrimidin-4-yl)amino)-N-cyclo-
3e The product was obtained as a
hexyl-4-methylbutanamide
(
).
yellow oil (390 mg, 82%) after chromatography on silica gel
(Et2O/EP 30:70). Rf (Et2O/EP 50:50) 0.5. H NMR (400 MHZ,
4.4.2.9:2-(allyl(2-(benzylsulfonyl)pyrimidin-4-yl)amino)-N-tert-butyl
butanamide (3i). The product was obtained as an yellow oil (370
1
CDCl3) δ 8.23 (d, 1H, J = 6.1 HZ), 7.30-7.26 (m, 2H), 7.25-7.22
(m, 3H), 6.48 (d, 1H, J = 6.1 HZ), 5.67-5.56 (m, 1H), 5.15 (d, 1
H , J = 10.6 HZ), 5.10 (d, 1H, J =17.2 HZ), 4.74 (d, 1H, J = 13.9
HZ), 4.56 (d, 1H, J =13.9 HZ), 4.55-4.46 (br s, 1H), 4.08 (d, 2 H ,
J = 4.3 HZ), 3.56-3.45 (m, 1H), 2.40-2.28 (br s, 1H), 1.74 (br d,
1H, J =11.1 HZ), 1.60 (br d, 1H, J =13.1 HZ), 1.53-1.39 (m, 3H),
1.22-1.13 (m, 2H), 1.12-0.98 (m, 3H), 0.89 (d, 3H, J = 6.6 HZ),
0.71 (d, 3H, J = 6.6 HZ). 13C NMR (100.6 MHZ, CDC13) δ 168.3,
mg, 85%) after chromatography on silica gel (Et2O/EP 30:70). Rf
1
(Et2O/EP 30:70) 0.2. H NMR (400 MHZ, CDCl3) δ 8.22 (d, 1H,
J = 6.3 HZ), 7.28-7.24 (m, 2H), 7.24-7.20 (m, 3H), 6.44 (d,
1H , J = 6.3 HZ), 6.40-6.34 (br s, 1H), 5.72-5.62 (m, 1H), 5.14 (d,
1H, J = 10.6 HZ), 5.02 (d, 1H, J = 17.4 HZ), 4.77-4.68 (m, 2H),
4.55 (d, 1H, J = 13.9 HZ), 4.21 (br d, 1H, J = 18.2 HZ), 3.86 (br
d, 1H, J = 18.2 HZ), 2.02-1.89 (m, 1H), 1.63-1.51 (m, 1H), 1.11
(s, 9H), 0.80 (t, 3H, J = 7.3 HZ). NMR 13C (100.6 MHZ, CDCl3) δ

7
169.1, 163.4, 162.2, 155.7, 132.1, 131.3, 128.8, 128.7, 127.3,
117.4, 107.1, 59.9, 57.3, 51.5, 47.2, 28.5, 21.8, 10.6. IR (thin
film): 2972, 1740, 1485, 1367, 1217 cm-1. HRMS Calculated for
C22H30N4O3S: 430.2039, found: 430.2043
phenylacetamide (4g). The product was obtained as a white
ACCEPTED MANUSCRIPT
solid (62 mg, 82%) after chromatography on silica gel (Et2O/EP
30:70). Rf (Et2O/EP 50:50) 0.5. MP = 168-169 °C. H NMR
1
(400 MHZ, CDCl3) δ 8.15 (d, 1H, J = 6.3 Hz), 7.32 (m, 5H), 6.54
(d, 1H, 6.3 Hz), 6.29 (s, 1H), 5.63 (d, 1H, J = 7.6 Hz), 5.43-5.31
(m, 1H), 4.96-4.91 (m, 2H), 4.02-3.87 (m, 2H), 3.80-3.70 (m,
1H), 1.86 (d, 2H, J = 11.9 Hz), 1.67-1.57 (m, 2H), 1.56-1.49 (m,
1H), 1.32-1.24 (m, 2H), 1.13-1.04 (m, 3H). 13C NMR (100.6
MHZ, CDCl3) δ 168.3, 161.6, 155.7, 143.8, 134.5, 132.2, 129.8,
129.1, 117.5, 116.2, 107.2, 62.7, 49.1, 48.9, 32.9, 24.8. IR (thin
film): 2933, 1740, 1580; 1384, 1227 cm-1. HRMS Calculated for
C22H25N5O: 375.2059, found: 375.2048.
4.5. Substitution of the sulfonyl group by CN
4.5.1. General procedure
To a solution of pyrimidine 3 (0.2 mmol) in dry DMF (2 mL)
was added KCN (1.2 equiv, 0.24 mmol). The reaction mixture
was stirred at 55 OC under argon for 24 h. After water addition
and extraction with Et2O, the cyanopyrimidines 4 were isolated
by flash column chromatography on silica gel.
4.5.2.5:
N-(4-chlorobenzyl)-2-((4-chlorobenzyl)(2-cyano-
4.5.2.1: 2-(allyl(2-cyanopyrimidin-4-yl)amino)-N-cyclohexyl-4-
methylpentanamide (4b). The product was obtained as a yellow
solid (60 mg, 85%) after chromatography on silica gel (Et2O/EP
pyrimidin-4yl)amino)butanamide (4h). The product was obtained
as a white solid (75 mg, 83%) after chromatography on silica gel
1
(Et2O/EP 40:60). Rf (Et2O/EP 50:50) 0.3. MP = 178-179 °C. H
1
20:80). Rf (Et2O/EP 50:50) 0.8. MP = 100-101 °C. H NMR
NMR (400 MHZ, CDCl3) δ 8.06 (d, 1H, J = 6.1 HZ), 7.23-7.17
(m, 4H), 7.07 (d, 2H, J = 7.6 HZ), 7.02 (d, 2H, J = 6.8 HZ), 6.62
(br s, 1H), 6.28 (d, 1H, J = 6.1 HZ), 5.26-5.06 (m, 1H), 4.88-4.71
(m, 1H), 4.66-4.45 (m, 1H), 4.37-4.23 (m, 2H), 2.05-1.96 (m,
1H), 1.73-1.59 (m, 1H), 0.87 (t, 3H, J = 7.1 HZ). 13C NMR
(100.6 MHZ, CDCl3) δ 169.9, 161.9, 156.2, 143.8, 136.2, 134.3,
133.5, 129.3, 129.1, 129.0, 127.3, 116.0, 107.4, 59.6, 48.4, 42.9,
23.9, 10.9. IR (thin film): 2937, 1744, 1587, 1384; 1249 cm-1.
HRMS Calculated for C23H21C12N5O: 453.1123, found:
453.1119.
(400 MHZ, CDCl3) δ 8.15 (d, 1H, J = 6.1 Hz), 6.50 (d, 1H, J =
6.1 Hz), 5.97 (d, 1H, J = 6.3 Hz), 5.76-5.61 (m, 1 H), 5.27-5.04
(m, 3H), 4.11 (d, 1H, J = 17.2 Hz), 3.94 (d, 1H, J = 17.2 Hz),
3.69-3.58 (m, 1H), 1.88-1.77 (m, 2H), 1.73-1.67 (m, 2H), 1.59-
1.39 (m, 4H), 1.31-1.21 (m, 2H), 1.15-1.07 (m, 2H), 1.04-0.98
(m, 1H), 0.88 (d, 3H, J = 6.6 Hz), 0.86 (d, 3H, J = 6.6 Hz). NMR
13C (100.6 MHZ, CDCl3) δ 168.9, 161.6, 155.7, 143.8, 132.1,
117.9, 1 16.1, 107.4, 55.9, 48.3, 47.3, 37.6, 32.9, 32.8, 25.4, 25.0,
24.7, 22.7, 22.6. IR (thin film): 2933, 1740, 1580, 1485, 1213
cm-1. HRMS Calculated for C20H29N5O: 355.2372, found:
355.2381.
4.5.2.6
:
2-(allyl(2-cyanopyrimidin-4-yl)amino)-N-tert-butyl
butanamide (4i). The product was obtained as a yellow oil (53
4.5.2.2: 2-(allyl(2-cyanopyrimidin-4-yl)amino)-N-cyclohexyl-
3-methylbutanamide (4e). The product was obtained as a white
solid (50 mg, 81%) after chromatography on silica gel (Et2O/EP
mg, 88%) after chromatography on silica gel (Et2O/EP 20:80). Rf
(Et2O/EP 50:50) 0.9. H NMR (400 MHZ, CDCl3) δ 8.15 (d, 1H,
1
J = 6.3
(m, 1H), 5.17 (d, 1H, 10.6
4.82 (br s, 1H), 4.13 (d, 1H, 16.4 H
H
Z), 6.50 (d, 1H, J = 6.3
Z), 5.10 (d, 1H, J = 17.4
Z), 4.00-3.87 (m, 1H), 2.05-
H
Z), 5.98 (br s, 1H), 5.76-5.61
1
20:80). Rf (Et2O/EP 50:50) 0.7. MP = 101-102 °C. H NMR
H
H
Z), 4.99-
(400 MHZ, CDCl3) δ 8.14 (d, 1H, J = 6.1
6.1 Z), 5.95 (s, 1H), 5.67-5.54 (m, 1H), 5.16 (d, 1H, J = 10.4
Z), 5.09 (d, 1H, J = 16.9 Z), 4.86-4.74 (m, 1H), 4.19 (br d, 1H,
J = 17.4 Z), 4.01 (dd, 1H, J = 17.4, 5.8
2.39-2.29 (m, 1H), 1.85 (d, 1H, J = 10.6
H
Z), 6.52 (d, 1H, J =
H
1.89 (m, 2H), 1.25 (s, 9H), 0.86-0.82 (m, 3H). 13C NMR (100.6
MHZ, CDCl3) δ 169.0, 161.5, 155.7, 143.8, 132.0, 117.8, 116.1,
107.3, 59.9, 51.6, 47.2, 28.7, 22.0, 10.7. IR (thin film): 2972,
1740, 1677, 1485, 1227 cm-1. HRMS Calculated for C16H23N5O:
301.1903, found: 301.1908.
H
H
H
H
H
Z), 3.70-3.59 (m, 1H),
Z), 1.72-1.60 (m, 2H),
1.58-1.47 (m, 2H), 1.31-1.21 (m, 2H), 1.18-1.11 (m, 2H), 1.01 (d,
1H, J = 10.6 Z), 0.95 (d, 3H, J = 6.6 Z), 0.74 (d, 3H, J = 6.6
Z). 13C NMR (100.6 MHZ, CDCl3) δ 168.3, 161.8, 155.6, 143.8,
H
H
H
131.8, 118.1, 116.2, 107.4, 63.7, 48.2, 46.9, 32.9, 32.7, 27.3,
25.4, 24.7, 24.6, 19.5, 18.9. IR (thin film): 2930, 1667, 1527,
1482, 1388 cm-1. HRMS Calculated for C19H27N5O: 341.2216,
found: 341.2219.
4.6. Substitution of the sulfonyl group by a dimethylmalonyl
ester group
4.6.1. General procedure
4.5.2.3: 2-((4-chlorobenzyl)(2-cyanopyrimidin-4-yl)amino)-N-
cyclohexyl-3methylbutanamide (4f). The product was obtained as
a yellow solid (60 mg, 82%) after chromatography on silica gel
To a solution of dimethylmalonate (1.2 equiv, 0.24 mmol) in dry
acetonitrile (0.1 M) at rt under argon was added Cs2CO3 (1.5
equiv, 0.3 mmol). After 30 min, pyrimidinesulfone 3 (0.2 mmol)
was added and the mixture was heated at 70°C for 48 h. After
water addition and extraction with CH2Cl2, the pyrimidines 5
were isolated by flash column chromatography on silica gel.
1
(Et2O/EP 30:70). Rf (Et2O/EP 50:50) 0.5. MP = 130-131 °C. H
NMR (400 MHZ, CDCl3) δ 8.03 (d, 1H, J = 6.1 HZ), 7.21-7.15
(m, 2H), 6.99-6.90 (m, 2H), 6.22 (d, 1H, J = 6.1 HZ), 6.05 (br s,
1H), 5.13-4.86 (m, 2H), 4.43 (d, 1H, J = 16.7 HZ), 3.68-6.56 (m,
1H), 2.45-2.31 (m, 1H), 1.89-1.81 (m, 1H), 1.74-1.47 (m, 4H),
1.31-1.21 (m, 2H), 1.16-1.04 (m, 3H), 0.96 (d, 3H, J = 6.8 HZ),
0.75 (d, 3H, J = 6.8 HZ). 13C NMR (100.6 MHZ, CDCl3) δ 168.2,
162.0, 155.9, 143.8, 134.0, 133.3, 129.1, 127.5, 116.1, 107.5,
64.1, 48.4, 47.5, 33.0, 32.8, 28.0, 25.4, 24.7, 19.1. IR (thin film):
2933, 1740, 1663, 1485, 1217 cm-1. HRMS Calculated for
C23H28ClN5O: 425.1982, found: 425.1974.
4.6.2.1: dimethyl 2-(4-((1-(4-chlorobenzylamino)-4-methyl-1-
oxopentan-2-yl)(allyl)amino) pyrimidin-2-yl)malonate (5a). The
product was obtained as a yellow oil (86 mg, 86%) after
chromatography on silica gel (Et2O/EP 50:50). Rf (Et2O/EP
1
50:50) 0.2. H NMR (400 MHZ, CDCl3) δ 8.12 (d, 1H, J = 6.3
HZ), 7.44 (br s, 1H), 7.12 (d, 2H, J = 8.3 HZ), 7.03 (d, 2H, J = 8.3
HZ), 6.29 (d, 1H, J = 6.3 HZ), 5.60-5.48 (m, 1H), 5.47-5.35 (br s,
1H), 5.10-5.03 (m, 2H), 4.87 (s, 1H), 4.30 (dd, 1H, JAB = 14.4,
5.3 HZ), 4.19 (dd, 1H, JAB = 14.4, 5.3 HZ), 4.09-4.00 (m, 1H),
3.70-3.67 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 1.85-1.75 (m, 1H),
1.60-1.54 (m, 1H), 1.50-1.41 (m, 1H), 0.84 (d, 3H, J = 6.3 HZ),
4.5.2.4: 2-(allyl(2-cyanopyrimidin-4-yl)amino)-N-cyclohexyl-2-

8
Tetrahedron
0.80 (d, 3H, J = 6.3
H
Z). 13C NMR (100.6 MHZ, CDCl3) δ
benzyl)-4-methylpentanamide (6a). The product was obtained as
ACCEPTED MANUSCRIPT
170.4, 167.5, 167.4, 161.9, 161.2, 156.1, 137.6, 132.6, 129.1,
128.4, 117.4, 103.8, 61.0, 54.0, 53.0, 46.8, 42.5, 36.4, 24.9, 22.6,
22.5. IR (thin film): 2954, 1740, 1587, 1367, 1217 cm-1. HRMS
Calculated for C25H31ClN4O5: 502.1983, found: 502.1995.
a yellow oil (35 mg, 75%) after chromatography on silica gel
1
(Et2O/EP 40:60). Rf (Et2O/EP 50:50) 0.3. H NMR (400 MHZ,
CDCl3) δ 8.03 (d, 1H, J = 6.1
(d, 2H, J = 8.3 Hz), 6.90 (d, 2H, J = 8.3
Z), 6.1 (d, 1H, J = 6.1 Z), 6.02-5.92 (br s, 1H), 5.69-5.57 (m,
1H), 5.10 (d, 1H, J = 12.1 Z), 5.06 (d, 1H, J =18.4 Z), 4.94-
4.80 (m, 1H), 4.16 (dd, 1H, J = 14.9, 6.1 Z), 4.09 (dd, 1H, J =
17.4, 5.6 Hz), 4.03 (dd, 1H, J = 14.9, 6.1 Z), 3.74 (br d, 1H, J =
17.4 Z), 2.16 (s, 3H), 1.83-1.74 (m, 1H), 1.44-1.31 (m, 2H),
0.78 (d, 3H, J = 6.3 Hz), 0.76 (d, 3H, J = 6.3
Z). 13C NMR
H
Z), 7.18 (d, 2H, J = 8.3
HZ), 6.96
H
Z), 6.85 (d, 2H, J = 8.3
H
H
4.6.2.2: dimethyl 2-(4-(allyl(1-(4-cyclohexylamino)-4-methyl-1-
oxopentan-2-yl)amino) pyrimidin-2-yl)malonate (5b). The
product was obtained as a yellow oil (80 mg, 87%) after
chromatography on silica gel (Et2O/EP 40:60). Rf (Et2O/EP
H
H
H
H
H
1
50:50) 0.3. H NMR (400 MHZ, CDCl3) δ 8.12 (d, 1H, J = 6.1
H
H
Z), 6.36 (br s, 1H), 6.29 (d, 1H, J = 6.1
5.53 (br s, 1H), 5.13 (d, 1H, J = 10.4 Z), 5.10 (d, 1H, J = 17.2
Z), 4.88 (s, 1H),4.11 (d, 1H, J = 17.9 Z), 3.81-3.76 (m, 1H),
H
Z), 5.76-5.61 (m, 1H),
(100.6 MHZ, CDCl3) δ 170.6, 164.9, 163.5, 158.3, 150.9, 136.4,
135.0, 133.1, 130.0, 128.7, 128.6, 121.9, 117.2, 99.6, 54.6, 47.3,
42.4, 37.1, 24.9, 22.8, 22.0, 20.8. IR (thin film): 2954, 1677,
1590, 1384, 1206 cm-1. HRMS Calculated for C27H31C1N4O:
462.2186, found: 462.2185.
H
H
H
3.74 (s, 3H), 3.73 (s, 3H), 3.62-3.54 (m, 1H), 1.84-1.72 (m, 2H),
1.66-1.47 (m, 5H), 1.46-1.30 (m, 1H), 1.23-1.14 (m, 3H), 1.08-
0.95 (m, 2H), 0.85 (d, 3H, J = 6.6
HZ), 0.81 (d, 3H, J = 6.6 HZ).
13C NMR (100.6 MHZ, CDCl3) δ 169.4, 167.5, 167.2, 161.8,
161.4, 156.1, 132.9, 117.8, 103.5, 61.2, 54.3, 53.0, 52.9, 48.3,
46.7, 36.9, 32.7, 32.5, 25.5, 25.2, 25.0, 24.9, 22.7, 22.5. IR (thin
film): 2933, 1740, 1583, 1370, 1217 cm-1. HRMS Calculated for
C24H36N4O5: 460.2686, found: 460.2696.
4.7.2.2: 2-(allyl(2-o-tolylpyrimidin-4-yl)amino)N-cyclohexyl-3-
methylpentanamide (6b). The product was obtained as a yellow
oil (30 mg, 70%) after chromatography on silica gel (Et2O/EP
40:60). Rf (Et2O/EP 60:40) 0.4. 1H NMR (400 MHZ, CDCl3)
δ 8.01 (d, 1H, J = 6.1
H
Z), 7.20-7.18 (m, 1H), 7.16 (d 1H, J = 8.1
H
Z), 7.12-7.07 (m, 1H), 7.04 (d, 1H, J = 8.1 Hz), 6.07 (d, 1H, J =
4.6.2.3: dimethyl 2-(4-(allyl(2-(cyclohexylamino)-2-oxoethyl)
amino) pyrimidin-2-yl)malonate (5c). The product was obtained
as a colorless oil (86 mg, 86%) after chromatography on silica
6.1
H
Z), 5.70-5.59 (m, 1H), 5.48 (d, 1H, J = 6.8
Z), 5.07 (d, 1H, J = 17.9 Z), 4.91 (br s, 1H), 4.09-3.95
(m, 1H), 3.78 (d, 1H, J = 17.7 Z), 3.57-3.47 (m, 1H), 2.13 (s,
HZ), 5.11 (d, 1H,
J = 13.4
H
H
H
1
gel (Et2O/EP 50:50). Rf (Et2O/EP 50:50) 0.2. H NMR (400
3H), 1.72-1.64 (m, 2H), 1.62-1.48 (m, 4H), 1.46-1.38 (m, 1H),
MHZ, CDCl3) δ 8.17 (d, 1H, J = 5.8
5.80-5.67 (m, 1H), 5.17 (d, 1H, J = 10.6
17.4 Z), 4.86 (s, 1H), 4.09-3.98 (m, 4H), 3.74 (s, 6H), 3.70-
3.58 (m, 1H), 1.79-1.72 (m, 2H), 1.63-1.57 (m, 2H), 1.55-1.49
(m, 1H), 1.27-1.21 (m, 2H), 1.10-0.99 (m, 3H). 13C NMR (100.6
MHZ, CDCl3) δ 166.7, 166.2, 161.0, 160.4, 155.4, 129.6, 117.0,
101.1, 60.3, 51.9, 51.2, 50.5, 47.4, 32.5, 25.5, 25.0. IR (thin
film): 2937, 1740, 1590, 1367, 1217 cm-1. HRMS Calculated for
C20H28N4O5: 404.2060, found: 404.2055.
H
Z), 6.39-6.15 (m, 2H),
1.36-1.27 (m, 1H), 1.25-1.16 (m, 2H), 1.07-1.01 (m, 1H), 0.95-
H
Z), 5.11 (d, 1H, J =
0.81 (m, 2H), 0.75 (d, 3H, J = 6.3 HZ), 0.74 (d, 3H, J = 6.3 HZ).
H
13C NMR (100.6 MHZ, CDCl3) δ 169.5, 164.4, 163.6, 158.2,
151.7, 133.2, 131.3, 130.8, 127.1, 125.5, 122.3, 117.2, 99.5, 54.4,
47.9, 47.0, 37.2, 33.0, 32.9, 25.6, 24.9, 24.8, 22. 6, 22.5, 16.5. IR
(thin film): 2930, 1740, 1590, 1381, 1217 cm-1. HRMS
Calculated for C26H36N4O: 420.2889, found: 420.2858.
4.7.2.3: 2-(allyl(2-phenylpyrimidin-4-yl)amino)N-cyclohexyl-3-
methylbutanamide (6c). The product was obtained as a yellow oil
(28 mg, 72%) after chromatography on silica gel (Et2O/EP
30:70). Rf (Et2O/EP 50:50) 0.5. H NMR (400 MHZ, CDCl3)
δ 7.98 (d, 1H, J = 6.1 Hz), 7.39-7.34 (m, 2H), 7.20-7.16 (m, 1H),
4.6.2.4: dimethyl 2-(4-(allyl(1-(cyclohexylamino)-3-methyl-1-
oxobutan-2-yl)amino)pyrimidin-2-yl)malonate (5e). The product
was obtained as a yellow oil (74 mg, 83%) after chromatography
1
1
on silica gel (Et2O/EP 40:60). Rf (Et2O/EP 50:50) 0.3. H NMR
(400 MHZ, CDCl3) δ 8.12 (d, 1H, J = 6.1
6.1 Z), 6.24 (br s, 1H), 5.69-5.57 (m, 1H), 5.15-5.08 (m, 2H),
4.88 (s, 1H), 4.85-4.74 (m, 1H), 4.06 (dd, 1H, J = 17.7, 5.6 Z),
4.00-3.95 (m, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.64-3.57 (m, 1H),
2.40-2.25 (m, 1H), 1.84-1.77 (m, 1H), 1.67-1.48 (m, 4H), 1.27-
H
Z), 6.31 (d, 1H, J =
7.12 (d, 2H, J = 7.6
2H), 5.10 (d, 1H, J = 7.8
4.41 (br s, 1H), 4.06-3.94 (m, 2H), 3.60-3.49 (m, 1H), 2.29-2.20
(m, 1H), 1.70 (br d, 1H, J = 11.6 Z), 1.62-1.55 (m, 2H), 1.53-
1.46 (m, 2H), 1.28-1.20 (m, 2H), 1.09-1.04 (m, 1H), 0.97-0.84
(m, 2H), 0.80 (d, 3H, J = 6.6 Z), 0.70 (d, 3H, J = 6.6
Z). 13C
NMR (100.6 MHZ, CDCl3) δ 168.9, 164.6, 163.8, 157.8, 153.3,
132.9, 129.5, 125.3, 122.2, 1175, 100.0, 63.0, 47.7, 47.0, 33.0,
32.7, 26.7, 25.5, 24.7, 24.6, 19.6, 19.1. IR (thin film): 2930,
1670, 1587, 1381, 1206 cm-1. HRMS Calculated for C24H32N4O:
392.2576, found: 392.2522.
H
Z), 6.11 (d, 1H, J = 6.1
H
Z), 5.71-5.46 (m,
H
H
Z), 5.07 (d, 1H, J = 15.7
H
Z), 4.61-
H
H
1.13(m, 3H), 1.07-0.96 (m, 2H), 0.91 (d, 3H, J = 6.6
H
Z), 0.73 (d,
H
H
3H, J = 6.6
H
Z). 13C NMR (100.6 MHZ, CDCl3) δ 168.9, 1676,
167.2, 161.9, 161.3, 156.0, 132.7, 117.8, 103.6, 62.9, 61.2, 53.0,
52.9, 48.2, 46.7, 32.8, 32.5, 26.4, 25.5, 25.1, 25.0, 19.9, 19.2. IR
(thin film): 2933, 1740, 1670, 1541, 1482 cm-1. HRMS
Calculated for C23H34N4O5: 446.2529, found: 446.2516.
4.7. Palladium catalyzed couplings of 3 with boronic acids
4.7.2.4: 2-(allyl(2-p-tolylpyrimidin-4-yl)amino)N-cyclohexyl-2-
phenylbutanamide (6d). The product was obtained as a white
solid (26 mg, 60%) after chromatography on silica gel (Et2O/EP
40:60). MP = 159-160°C. Rf (Et2O/EP 50:50) 0.3. 1H NMR (400
4.7.1. General procedure
To a solution 0.05 M of (benzylsulfonyl)pyrimidine 3 (0.1 mmol)
in toluene (2 mL) were successively added under inert
atmosphere Pd(OAc)2 (5.0 mol %), triphenylphosphine (15 mol
%) followed by the boronic acid (1.2 equiv, 0.12 mmol) and
Cs2CO3 (1.5 equiv, 0.15 mmol). The reaction mixture was stirred
under reflux for 40 h. After water addition and extraction with
CH2Cl2, the pyrimidines 6 were isolated by flash column
chromatography on silica gel.
MHZ, CDCl3) δ 7.98 (d, 1H, J = 6.1
H
Z), 7.30-7.18 (m, 5H), 7.11
Z), 7.00 (d, 2H, J = 8.3 Z), 6.28 (s, 1H), 6.15
Z), 5.46 (d, 1H, J = 7.3 Z) 5.43-5.32 (m, 1H),
(d, 2H, J = 8.3
(d, 1H, J = 6.1
H
H
H
H
4.99-4.87 (m, 2H), 4.01-3.85 (m, 2H), 3.75-3.65 (m, 1H), 2.27(s,
3H), 1.85-1.72 (m, 2H), 1.60 (br d, 2H, J = 11.8 Z), 1.53 (br d,
H
1H, J =12.6
HZ), 1.26 (br d, 2H, J = 12.6 HZ), 1.05-0.90 (m, 3H).
13C NMR (100.6 MHZ, CDCl3) δ 168.7, 164.7, 163.8, 157.7,
4.7.2.1:
2-(allyl(2-p-tolylpyrimidin-4-yl)amino)N-(4-chloro
151.0, 135.5, 134.5, 133.5, 129.9, 129.6, 128.8, 128.5, 121.8,

9
116.8, 99.8, 61.4, 48.9, 32.9, 32.8, 25.5, 24.8, 21.0. IR (thin
H
Z). 13C NMR (100.6 MHZ, CDCl3) δ 169.4, 164.6, 163.6,
ACCEPTED MANUSCRIPT
film): 2930, 1740, 1587, 1384, 1206 cm-1. HRMS Calculated for
C28H32N4O: 440.2576, found: 440.2562.
159.6 (JC-F = 244.4
H
Z), 158.0, 148.9 (JC-F = 2.2
H
Z), 133.0, 1235
HZ), 99.9, 54.8, 47.8,
(JC-F = = 8.1 Z), 117.4, 116.2 (JC-F = 23.4
H
47.1, 37.1, 32.9, 32.8, 25.5, 24.9, 24.7, 24.6, 22.6, 22.5. IR (thin
film): 2933, 1737, 1590, 1503, 1192 cm-1. HRMS Calculated for
C25H33FN4O: 424.2638, found: 424.2620.
4.7.2.5:
2-((4-chlorobenzyl)(2-o-tolylpyrimidin-4-yl)amino)N-
cyclohexyl-2-methylpentanamide (6e). The product was obtained
as a yellow oil (35 mg, 69%) after chromatography on silica gel
(Et2O/EP 40:60). Rf (Et2O/EP 50:50) 0.3. H NMR (400 MHZ,
1
4.7.2.9: 2-(allyl(2-(4-methoxyphenyl)pyrimidin-4-yl)amino)-N-
cyclohexyl-4-methylbutanamide (6i). The product was obtained
as a yellow oil (32 mg, 75%) after chromatography on silica gel
CDCl3) δ 7.94 (d, 1H, J = 6.1
1H, J = 7.3 Z), 7.08 (d, 1H, J = 8.1
Z), 5.85 (d, 1H, J = 6.1 Z), 5.54 (br s, 1H), 5.06-4.97 (br s,
H
Z), 7.23-7.19 (m, 4H), 7.12 (d,
H
H
Z), 6.97 (d, 2H, J = 7.6
1
H
H
(Et2O/EP 50:50). Rf (Et2O/EP 50:50) 0.2. H NMR (400 MHZ,
1H), 4.74-4.59 (m, 1H), 4.50-4.36 (m, 1H), 3.58-3.47 (m, 1H),
2.16 (s, 3H), 1.78-1.65 (m, 2H), 1.63-1.49 (m, 4H), 1.34-1.16 (m,
4H), 1.09-1.02 (m, 1H), 0.94-0.84 (m, 2H), 0.74 (d, 3H, J = 5.3
CDCl3) δ 7.98 (d, 1H, J = 6.1
6.85 (m, 2H), 6.10 (d, 1H, J = 6.1
5.12-5.04 (m, 2H), 4.58 (br s, 1H), 3.99 (br d, 2H, J = 4.0
Z), 3.75 (s, 3H), 3.62-3.51 (m, 1H), 2.34-2.20 (m, 1H), 1.72
(d, 1H, J= 11.6 Z), 1.63-1.56 (m, 2H), 1.54-1.46 (m, 2H),
1.30-1.21 (m, 2H), 1.10-1.03 (m, 1H), 0.97 (d, 1H, J = 11.6
Hz,), 0.91-0.86 (m, 1H), 0.83 (d, 3H, J = 6.6 Z), 0.72 (d,
Z). 13C NMR (400 MHZ, CDCl3) δ 168.9, 164.9,
156.8, 146.7, 132.9, 122.9, 117.5, 114.4, 99.9,
H
Z), 7.07-7.02 (m, 2H), 6.89-
H
Z), 5.69-5.54 (m, 2H),
H
Z), 0.70 (d, 3H, J = 5.3
H
Z). 13C NMR (100.6 MHZ, CDCl3)
H
δ 169.3, 164.3, 163.9, 158.5, 151.6, 135.6, 132.9, 131.4, 130.8,
128.9, 127.5, 127.1, 125.6, 122.3, 99.7, 55.1, 48.0, 47.9, 37.5,
33.0, 32.9, 25.5, 25.1, 24.8, 22.8, 22.3, 16.6. IR (thin film): 2930,
1674, 1590, 1489, 1182 cm-1. HRMS Calculated for
C30H37ClN4O: 504.2656, found: 504.2674.
H
H
3H, J = 6.6
163.9, 157.7
H
,
4.7.2.6:
2-((4-chlorobenzyl)(2-o-tolylpyrimidin-4-yl)amino)N-
63.2, 55.6, 47.7, 46.9, 33.0, 32.7, 26.7, 25.5, 24.7, 24.6,
19.7, 19.1. IR (thin film): 2933, 1744, 1590, 1384, 1206 cm-1.
HRMS Calculated for C25H34N4O2: 422.2682, found:
422.2691.
cyclohexyl-2-methylpentanamide (6f). The product was obtained
as a yellow oil (33 mg, 74%) after chromatography on silica gel
(Et2O/EP 30:70). Rf (Et2O/EP 60:40) 0.5. H NMR (400 MHZ,
1
CDCl3) δ 8.00 (d, 1H, J = 6.1
(d, 2H, J = 8.6 Z), 6.12 (d, 1H, J = 6.1
5.12 (d, 1H, J = 11.1 Z), 5.08 (d, 1H, J = 17.7
1H), 4.05 (d, 1H, J = 16.9 Z), 3.81 (d, 1H, J = 16.9
H
Z), 7.30 (d, 2H, J = 8.6
Z), 5.71-5.59 (m, 2H),
Z), 4.97 (br s,
Z), 3.59-
HZ), 7.07
H
H
4.7.2.10: 2-(allyl(2-(2-methoxyphenyl)pyrimidin-4-yl)amino)-N-
cyclohexyl-4-methylpentanamide (6j). The product was obtained
as a yellow oil (28 mg, 65%) after chromatography on silica gel
H
H
H
H
1
3.49 (m, 1H), 1.75-1.66 (m, 2H), 1.62-1.54 (m, 2H), 1.53-1.43
(Et2O/EP 50:50). Rf (Et2O/EP 50:50) 0.2. H NMR (400 MHZ,
(m, 3H), 1.40-1.34 (m, 1H), 1.28-1.17 (m, 2H), 1.11-1.03 (m,
CDCl3) δ 7.99 (d, 1H, J = 6.1
7.09 (d, 1H, J = 7.6 Z), 6.96-6.89 (m, 2H), 6.07 (d, 1H, J =
6.1 Z), 5.78 (d, 1H, J = 7.3 Z), 5.70-5.59 (m, 1H), 5.11 (d,
1H, J = 10.1 Z), 5.07 (d, 1H, J = 17.4 Z), 4.95 (br s, 1H),
4.02 (dd, 1H, J = 17.7, 4.0 Z), 3.77 (d, 1H, J = 17.7 Z),
3.70 (s, 3H), 3.59-3.48 (m, 1H), 1.74-1.55 (m, 5H), 1.54-
1.41 (m, 2H), 1.38-1.30 (m, 1H), 1.27-1.16 (m, 2H), 1.08-
1.02 (m, 1H), 1.00-0.84 (m, 2H), 0.75 (d, 3H, J = 6.8 Hz),
0.72 (d, 3H, J = 6.8 Hz). 13C NMR (100.6 MHZ, CDCl3)
HZ), 7.14 (t, 1H, J = 7.6 HZ),
1H), 0.95-0.83 (m, 2H), 0.79 (d, 3H, J = 6.3
H
Z), 0.78 (d, 3H, J =
H
6.3
H
Z). 13C NMR (100.6 MHZ, CDCl3) δ 169.5, 164.3, 163.6,
H
H
157.8, 151.6, 132.9, 130.6, 129.6, 123.6, 117.4, 100.1, 54.9, 47.9,
47.1, 37.1, 32.9, 32.7, 25.5, 24.9, 24.7, 24.6, 22.6, 22.4. IR (thin
film): 2937, 1740, 1590, 1370, 1213 cm-1. HRMS Calculated for
C25H33ClN4O: 440.2343, found: 440.2336.
H
H
H
H
4.7.2.7: 2-(allyl(2-(3,4-dichlorophenyl)pyrimidin-4-yl)amino)N-
cyclohexyl-4-methylpentanamide (6g). The product was obtained
as a yellow oil (33 mg, 70%) after chromatography on silica gel
δ
169.6, 164.4, 163.9, 158.0, 151.9, 142.3, 133.2, 126.3, 123.2,
121.1, 117.2, 113.2, 99.6, 56.2, 54.4, 47.9, 47.0, 37.0, 33.0,
1
(Et2O/EP 30:70). Rf (Et2O/EP 60:40) 0.5. H NMR (400 MHZ,
32.8, 25.6, 24.8, 24.7, 22.6, 22.4. IR (thin film): 2933, 1677,
CDCl3) δ 7.99 (d, 1H, J = 6.1
(d, 1H, J = 2.5 Z), 7.01 (dd, 1H, J = 8.6, 2.5
= 6.1 Z), 5.73-5.57 (m, 2H), 5.14 (d, 1H, J = 11.4
1H, J = 18.2 Hz), 5.05-4.92 (br s, 1H), 4.10-3.98 (m, 1H), 3.83
(br d, 1H, J = 16.4 Z), 3.61-3.50 (m, 1H), 1.77-1.67 (m, 2H),
H
Z), 7.4.1 (d, 1H, J = 8.6
Z), 6.14 (d, 1H, J
Z), 5.09 (d,
H
Z), 7.27
1499, 1388, 1206 cm-1. HRMS Calculated for C26H36N4O2:
H
H
436.2838, found: 436.2830.
H
H
4.7.2.11:
2-((4-chlorobenzyl(2-(2-methoxyphenyl)pyrimidin-4-
H
yl)amino)-N-cyclohexyl-4-methylpentanamide (6k). The product
1.63-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.42-1.35 (m, 1H), 1.24-
was obtained as a green oil (32 mg, 61%) after chromatography
on silica gel (Et2O/EP 50:50). Rf (Et2O/EP 50:50) 0.2. H NMR
1
1.17 (m, 2H), 1.11-1.05 (m, 1H), 0.96-0.84 (m, 2H), 0.80 (d, 3H,
J = 6.3
H
Z), 0.79 (d, 3H, J = 6.3 Hz). 13C NMR (100.6 MHZ,
(400 MHZ, CDCl3) δ 7.92 (d, 1H, J= 5.8
3H), 7.15-7.11 (m, 1H), 6.99 (d, 2H, J= 8.8
2H, J= 8.8 Z), 5.95-5.87 (br s, 1H), 5.85 (d, 1H, J = 5.8
Z), 5.04 (br s, 1H), 4.65 (d, 1H, J= 16.4 Z), 4.49-4.36 (m,
H
Z), 7.22-7.18 (m,
CDCl3) δ 169.3, 164.0, 163.7, 157.9, 151.9, 133.0, 132.9, 130.8,
129.1, 124.4, 121.9, 117.5, 100.4, 55.0, 47.9, 47.2, 37.2, 32.9,
32.7, 25.4, 24.9, 24.7, 24.6, 22.5. IR (thin film): 2933, 1740,
1590, 1337, 1213 cm-1. HRMS Calculated for C25H32Cl2N4O:
474.1953, found: 474.1946.
H
Z), 6.96 (d,
H
H
H
1H), 3.73 (s, 3H), 3.59-3.48 (m, 1H), 1.77-1.67 (m, 2H),
1.63-1.50 (m, 4H), 1.35-1.28 (m, 2H), 1.27-1.21 (m, 2H),
1.10-1.04 (m, 1H), 0.98-0.86 (m, 2H), 0.73 (d, 3H, J = 6.3
Hz), 0.70 (d, 3H, J = 6.3 Hz). 13C NMR (100.6 MHZ, CDCl3) δ
169.4, 164.4, 164.0, 158.3, 151.9, 142.2, 135.8, 132.9, 129.9,
127.5, 126.4, 123.2, 121.2, 113.3, 99.9, 56.2, 55.1, 48.0, 47.9,
37.3, 33.0, 32.8, 25.6, 25.1, 24.8, 22.7, 22.4. IR (thin film):
2933, 1740, 1594, 1384, 1206 cm-1. HRMS Calculated for
C30H37C1N4O2: 520.2605, found: 520.2615
4.7.2.8:
2-(allyl(2-(4-fluorophenyl)pyrimidin-4-yl)amino)N-
cyclohexyl-4-methylpentanamide (6h). The product was obtained
as a yellow oil (31 mg, 73%) after chromatography on silica gel
1
(Et2O/EP 30:70). Rf (Et2O/EP 60:40) 0.5. H NMR (400 MHZ,
CDCl3) δ 8.00 (d, 1H, J = 6.1
(m, 2H), 6.10 (d, 1H, J = 6.1
J = 12.1 Z), 5.08 (d, 1H, J = 18.2
(br d, 1H , J = 17.7 Z), 3.80 (br d, 1H, J = 17.7
H
H
Z), 7.11-7.06 (m, 2H), 7.05-6.99
Z), 5.72-5.58 (m, 2H), 5.13 (d, 1H,
Z), 5.03-4.92 (m, 1H), 4.04
Z), 3.60-3.50
H
H
H
H
4.7.2.12: 2-((2-(4-acetylphenyl)pyrimidin-4-yl)(allyl)amino)-N-
cyclohexyl-2-phenylacetamide (6l). The product was obtained as
a yellow oil (30 mg, 63%) after chromatography on silica gel
(m, 1H), 1.75-1.69 (m, 2H),1.62-1.56 (m, 2H), 1.53-1.45 (m,
3H), 1.39-1.35 (m, 1H), 1.27-1.20 (m, 2H), 1.09-1.03 (m, 1H),
1
0.95-0.84 (m, 2H), 0.79 (d, 3H, J = 6.3
H
Z), 0.77 (d, 3H, J = 6.3
(Et2O/EP 40:60). Rf (Et2O/EP 40:60) 0.2. H NMR (400 MHZ,

10
Tetrahedron
CDCl3) δ 7.98 (d, 1H, J= 6.1
7.29-7.23 (m, 5H), 7.20 (d, 2H, J = 7.8
6.21 (d, 1H, J = 6.1 Z), 5.52 (br d, 1H, J= 8.8
HZ), 7.93 (d, 2H, J = 7.8 HZ), 4.9. General procedure for the one-pot three-step formation of
ACCEPTED MANUSCRIPT
H
Z), 6.27 (br s, 1H), diaminopyrimidines 7.
H
H
Z), 5.43-5.32
To a solution of the aldehyde (l.0 mmol) in toluene (1 mL) under
argon was successively added the amine (l.0 mmol), the
isocyanide (l.0 mmol), and 1a (l.0 mmol). The resulting mixture
was heated at 80°C for 3 days before adding dichloromethane (l
mL) at room temperature. The mixture was treated with 3 equiv of
m-CPBA (3.0 mmol) and left at room temperature for 5 h. The
second amine (3.0 equiv, 3.0 mmol) was then added and the
mixture was left at room temperature for 20 min (time long-
enough to destroy the remaining m-CPBA) before increasing the
temperature up to 110°C, which led to the distillation of the DCM
out of the reaction mixture. After 7 hours, toluene was evaporated
under reduced pressure and the crude material was purified by
flash chromatography on silica gel. This procedure was applied to
the preparation of 7a, 7b and 7h which were obtained in 46, 43
and 48% isolated yields.
(m, 1H), 4.93-4.85 (m, 1H), 4.01-3.87 (m, 1H), 3.77-3.66 (m,
1H), 2.52 (s, 3H), 1.85-1.72 (m, 2H), 1.63-1.48 (m, 3H), 1.29-
1.22 (m, 2H), 1.06-0.92 (m, 3H). 13C NMR (100.6 MHZ,
CDCl3) δ 196.9, 168.6, 164.0, 163.9, 157.5, 157.2, 135.2, 133.8,
133.2, 130.0, 129.6, 128.9, 128.6, 121.8, 117.0, 100.6, 61.9,
49.1, 48.7, 32.8, 32.5, 26.6, 25.4, 24.8, 24.7. IR (thin film):
2933, 1737, 1594, 1489, 1213 cm-1. HRMS Calculated for
C29H32N4O2: 468.2525, found: 468.2539.
4.7.2.13:
2-((4-chlorobenzyl(2-(4-ethylphenyl)pyrimidin-4-
yl)amino)-N-cyclohexyl-3-methylbutanamide (6m). The product
was obtained as a green oil (39 mg, 77%) after chromatography
1
on silica gel (Et2O/EP 30:70). Rf (Et2O/EP 50:50) 0.4. H NMR
(400 MHZ, CDCl3) δ 7.98 (d, 1H, J= 5.8 Hz), 7.19 (d, 2H,
J
=
H
8.1
H
Z), 7.14 (d, 2H, J = 8.3
= 8.3 Z), 5.82 (d, 1H, J= 5.8 Hz), 5.64
Z), 4.66 (br s, 1H), 4.45 (d,
Z), 3.59-3.48 (m, 1H), 2.60 (q, 2H, J = 7.6
Z), 2.35-2.19 (m, 1H), 1.75-1.67 (m, 1H), 1.64-1.49 (m,
4H), 1.26-1.13 (m, 5H), 1.11-1.05 (m, 1H), 0.99-0.89 (m,
2H), 0.81 (d, 3H, J = 6.3 Hz), 0.69 (d, 3H, J = 6.3
Z). 13
HZ), 7.04 (d, 2H, J = 8.1
Z), 6.93 (d, 2H,
J
H
(br s, 1H), 4.76 (d, 1H, J= 17.4
1H, J = 17.4
H
H
H
Acknowledgments
We thank ENSTAParistech for financial support and the
Ministry of higher education and scientific research of Algeria
for scholarship.
H
C
NMR (100.6 MHZ, CDCl3) δ 168.8, 164.8, 164.0, 158.1, 151.1,
141.2, 135.3, 132.8, 128.8, 128.7, 127.7, 121.9, 100.6, 63.7,
47.8, 47.5, 33.1, 32.8, 28.4, 27.3, 25.5, 24.7, 19.6, 19.2, 15.8.
IR (thin film): 2933, 1737, 1594, 1489, 1208 cm-1. HRMS
Calculated for C30H37C1N4O: 504.2656, found: 504.2642.
References and notes
1. Ait Sidhoum, M.; El Kaïm, L.; Grimaud, L. Synlett 2012, 23, 632-
636.
4.7.2.14: 2-((4-chlorobenzyl(2-(4-tert-butylphenyl)pyrimidin-4-
yl)amino)-N-cyclohexyl-3-methylbutanamide (6n). The product
was obtained as a green oil (43 mg, 81%) after chromatography
2. For recent reviews on the biological properties of pyrimidines: a)
Sahu, M.; Siddiqui, N. Int. J. Pharm. Sci. 2016, 8, 8-21. b)
Sharma, V.; Chitranshi, N.; Agarwal, A. K. Int. J. Med. Chem.
2014, 1-31. c) Jain, K. S.; Arya, N.; Inamdar, N. N.; Auti, P. B.;
Unawane, S. A.; Puranik, H. H.; Sanap, M. S.; Inamke, A. D.;
Mahale, V. J.; Prajapati C. S.; Shishoo, C. J. Curr. Topics in. Med.
Chem. 2016, 16, 3133-3174.
3. For a review on anticancer activities of aminopyrimidines see: a)
Koroleva, E.V.; Ignatovich, Z .I.; Sinyutich, Y.V.; Gusak, K. N.
Russ. J. Org. Chem. 2016, 52, 139-177. For selected examples
see: b) Verma, A. K.; Kumari, R.; Sing, A. K.; Sharma, B. B.;
Martin, A.; Kant, R. Int. Res. J. Pharm. 2014, 5, 922. c) Huang,
S.; Li, R. ; Connolly, P. J. ; Xu G. ; Gaul, M. D.; Emanuel, S.
L. ; Lamontagne, K. R.; Greenberger, L. M. Bioorg. Med. Chem.
Lett. 2006, 16, 6063-6066. d) Kim, L. C.; Rix, U.; Haura, E. B.
Expert Opinion on Investigational Drugs, 2010, 19, 415-425.
4. a) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem. Int. Ed. 2005,
44, 7961-7964. b) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble,
J. Org. Lett. 2006, 8, 4019-4021. c) El Kaim, L.; Gizolme, M.;
Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169-4180. d)
Barthelon, A.; El Kaïm, L.; Gizolme, M.; Grimaud, L. European
J. Org. Chem. 2008, 5974-5987. For some reviews: e) El Kaïm,
L.; Grimaud, L. Mol. Diversity 2010, 14, 855-867.f) El Kaïm, L.;
Grimaud, L. Eur. J. Org. Chem. 2014 , 7749–7762.
5. For palladium catalyzed substitution using alkyne see: a) Shook,
B. C.; Chakravarty, D.; Jackson, P. F. Tetrahedron Lett. 2009, 50,
1013-1015. b) Baralle, A.; Yorimitsu, H.; Osuka, A. Chem. Eur. J.
2016, 22, 10768-10772. For palladium and nickel catalyzed
substitution using organozinc see: c) Metzger, A.; Melzig, L.;
Despotopoulou, C.; Knochel, P. Org. Lett. 2009, 11, 4228- 4231.
d) Koshiba, T.; Miyazaki, T.; Tokuyama, H.; Fukuyama, T.
Heterocycles 2009, 77, 233-239. e) Melzig, L.; Metzger, A.;
Knochel, P. Chem. Eur. J. 2011, 17, 2948-2956. For a palladium
catalyzed substitution using boronic acids: f) Koley, M.; Wimmer,
L.; Schnuerch, M.; Mihovilovic, M. D. J. Heterocyclic Chem.
2013, 50, 1368-1373
1
on silica gel (Et2O/EP 30:70). Rf (Et2O/EP 50:50) 0.5. H NMR
(400 MHZ, CDCl3) δ 7.89 (d, 1H, J = 6.1
8.6 Z), 7.14 (d, 2H, J = 8.3 Z), 7.05 (d, 2H, J = 8.6
6.92 (d, 2H, = 8.3 Z), 5.82 (d, 1H, J = 6.1
1H), 4.73 (d, 1H, J = 17.4 Z), 4.61 (br s, 1H), 4.62 (d, 1H,
17.4 Z), 3.57-3.46 (m, 1H), 2.32-2.19 (m, 1H), 1.75-1.66
H
Z), 7.38 (d, 2H,
J
=
H
H
H
Z),
J
H
H
Z), 5.61 (br s,
H
J
=
H
(m, 1H), 1.64-1.48 (m, 4H), 1.27 (s, 9H), 1.23-1.18 (m, 2H),
1.12-1.05 (m, 1H), 1.00-0.92 (m, 2H), 0.77 (d, 3H, J = 6.3
H
Z), 0.68 (d, 3H, J = 6.3 H
Z). 13C NMR (100.6 MHZ, CDCl3)
δ 168.8, 164.8, 164.0, 158.2, 150.9, 148.1, 135.2, 132.8, 128.7,
127.7, 126.4, 121.5, 100.0, 63.6, 47.9, 47.3, 34.5, 33.2, 32.8, 32.5
, 27.2, 25.5, 24.7, 19.6, 19.2. IR (thin film): 2933, 1674, 1594,
1384, 1210 cm-1. HRMS Calculated for C32H41C1N4O:
532.2969, found: 532.2984.
4.8. General procedure for one-pot formation of
diaminopyrimidines 7 from 2
To a 0.1 M DCM/toluene (1:1) solution of Ugi-Smiles adduct 2
(1.0 mmol) is added 3.0 equiv of m-CPBA (3.0 mmol). The
reaction mixture was stirred under argon at rt for 2 h. Then amine
(3.0 equiv) was added and the mixture left further 20 min at rt
before raising the temperature to 110°C (distillation of the
DCM). After 7 hours, the toluene was evaporated under reduced
pressure and the crude material was purified by flash
chromatography on silica gel. This procedure was applied for all
diaminopyrimidines 7 presented in Table 6.
6. a) Rostami, A.; Akradi, J. Tetrahedron Lett. 2010, 51, 3501-3503.
b) Venkat-Reddy, C.; Verkade, J. G. J. Mol. Catal. A: Chem.
2007, 272, 233-240. c) Kirihara, M.; Yamamoto, J.; Noguchi, T.;
Hirai, Y. Tetrahedron Lett. 2009, 50, 1180-1183.
7. a) Torres, E.; Chen, Y.; Kim, I.-C.; Fuchs, P. L. Angew. Chem.,
Int. Ed. 2003, 42, 3124-3133.(b) Weaver, J. D.; Ka, B. J.; Morris,

11
D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132,
12179-12181. c) Andrisano, R.; Angeloni, A. S.; Fini, A.
Tetrahedron 1972, 28, 2681-2688.
ACCEPTED MANUSCRIPT
8. a) Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S. J. Chem. Soc.,
Perkin Trans. 1 1984, 1839-1845. b) Goebel, R. J.; Adams, A. D.;
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Cameron, K. S.; Hamilton, W.; Kerr, J.; Kinghorn, E.; McGarry,
G.; Robinson, J.; Scullion, P.; Uitdehaag, J. C. M.; Zeeland, M. v.;
Potin, D.; Saniere, L.; Fouquet, A.; Chevallier, F.; Deronzier, H.
Dorleans, C.; Nicolai, E. Bioorg. Med. Chem. Lett. 2010, 20,
4447-4450.
9. a) Yamane, A.; Matsuda, A.; Ueda, T. Chem. Pharm. Bull. 1980,
28, 150-156. b) Lapachev, V. V.; Zagulyeva, O. A.; Petrenko, O.
P.; Bychkov, S. F.; Mamaev, V. P. Chem. Het. Comp. 1984, 20,
676-680. c) P. Shang-Shing Chou, Hsin-I Hsieh, Chia-Cheng
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10. Liebeskind, L. S; Srogl, J. Org. lett. 2002, 4, 979 - 981 Koley, M.;
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Chem. 2011, 10, 1972 -1979
11. Liu, J. ; Robins M. J. Org. Lett.. 2005, 7, 1149-1151.
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