Ugi-smiles coupling of thiouracil derivatives towards 2,4-diamino pyrimidines

Article abstract of DOI:10.1055/s-0031-1290347

Diaminopyrimidines could be synthesized via a multicomponent coupling starting from S-alkyl thiouracil derivatives. The synthetic strategy based upon an Ugi-Smiles coupling, and subsequent oxidation of the adducts affords a versatile platform for the prep

Full text of DOI:10.1055/s-0031-1290347

632
LETTER
Ugi–Smiles Coupling of Thiouracil Derivatives towards
2,4-Diamino Pyrimidines
Multicomponent
Acce
a
i
d
amino
P
yrim
j
idines id Ait Sidhoum, Laurent El Kaïm,* Laurence Grimaud*
Laboratoire DCSO ENSTA-Polytechnique-CNRS, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées,
32 Bd Victor, 75739 Paris, Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: grimaud@dcso.polytechnique.fr
Received 4 November 2011
S-Benzyl thiouracil, chosen as a model for this study, was
prepared through benzylation of thiouracil with benzyl
and fluorobenzyl chlorides under standard conditions.
The presence of the electron-donating thioether moiety on
Abstract: Diaminopyrimidines could be synthesized via a multi-
component coupling starting from S-alkyl thiouracil derivatives.
The synthetic strategy based upon an Ugi–Smiles coupling, and
subsequent oxidation of the adducts affords a versatile platform for
the preparation of various diaminopyrimidines with five points of the pyrimidine ring does not disrupt the Ugi–Smiles cou-
diversity. The whole sequence may be performed as a one-pot pro-
cess.
plings as shown by the various aminopyrimidines 1 pre-
pared from a series of amines, aldehydes, and isocyanides
Key words: Ugi–Smiles, thiouracil, isocyanide, diaminopyrim-
idines, SNAr
(Table 1). Good yields are obtained except with isocya-
noesters (Table 1, entries 4–6) in agreement with their
lower reactivity.
The ability of the thioether group of 1 to serve as a plat-
form for diaminopyrimidines was next examined. For this
purpose, the thioethers could be transformed into the cor-
responding sulfones, which are good leaving groups. Var-
ious oxidizing agents have been reported for the
conversion of thioethers into sulfones. Conditions allow-
ing a one-pot oxidation–substitution sequence were re-
quired in order to construct the fastest possible means of
access to diaminopyrimidine scaffolds. In terms of side-
product formation, hydrogen peroxide appears to be the
best choice.9 However, its use generally requires lengthy
optimization due to the need for a metal catalyst, and so
MCPBA was selected for its broad scope and simple
use;10 the resulting benzoic acid not being expected to
compete with the amines added in the subsequent step.
Diaminopyrimidines, which are involved in many bio-
chemical pathways including DNA biosynthesis, have the
ability to inhibit a large variety of protein kinases1 dis-
playing a wide range of biological activities such as anti-
cancer,2 antispychotic,3 or anti-inflammatory.4 Their
syntheses generally rely on nucleophilic aromatic substi-
tution performed on chloropyrimidines. The latter are pre-
pared by the transformation of hydroxy derivatives using
activating agents such as POCl3. A few years ago, we dis-
closed a new Ugi-type coupling for the synthesis of
anilines5 and heteroaromatic amines6 from an electron-
deficient phenol in one step. An appropriate choice of
reagent could allow the synthesis of 2,4-diaminopyrim-
idines,7 with a structure close to cytosine and uracil deriv-
atives. For instance, this reaction performed using
thiouracil would afford 4-amino-2-mercaptopyrimidines
which could be further transformed into the correspond-
ing diaminopyrimidines via an activation of the thio func-
tionality and subsequent nucleophilic aromatic
substitution.8 Herein, we wish to present a sequential mul-
ticomponent access to diaminopyrimidines starting with
S-alkyl thiouracils (Scheme 1).
This oxidation step was then tested with thioether 1g us-
ing three equivalents of MCPBA. Various solvents were
evaluated for this purpose: methanol, toluene, and dichlo-
romethane. The latter gave the best results with 95% iso-
lated yield in 30 minutes at room temperature compared to
90% over five hours in methanol and 70% over six hours
in toluene. A reductive workup is generally required when
using MCPBA in order to destroy the remaining oxidizing
agent and to suppress explosive hazards. However,
R4
R4
OH
N
R5
R5
R2
R1
CONHR3
NHR7
N
N
CONHR3
N
N
R4CHO
+
1) oxidation
at sulfur
N
R2
R1
R2
R1
N
N
SR6
2) R7NH2
Ugi–Smiles
SR6
R5NH2
R3NC
Scheme 1 Attempted Ugi–Smiles couplings of thiouracil
SYNLETT 2012, 23, 632–636
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 10.02.2012
DOI: 10.1055/s-0031-1290347; Art ID: D62811ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Multicomponent Access to 2,4-Diamino Pyrimidines
633
Table 1 Synthesis of Aminopyrimidines 1
R3
N
CONHR4
OH
R2CHO
MeOH
N
N
N
N
R2
+
R3NH2
Δ
S
S
R4NC
R1
R1
1
Entry
R1
H
H
H
R2
R3NH2
AllNH2
AllNH2
AllNH2
R4NC
Product
1a
Yield (%)
1
2
3
i-Bu
i-Bu
H
4-ClBnNC
CyNC
91
86
72
1b
CyNC
1c
4
5
H
H
H
H
AllNH2
1d
1e
45
47
MeO2C
MeO2C
NC
NC
MeO
NH2
NH2
6
7
H
H
F
H
1f
1g
1h
1i
51
72
72
85
77
MeO
AllNH2
MeO
MeO2C
NC
Ph
i-Bu
Ph
Ph
CyNC
8
4-ClBnNC
CyNC
NH2
NH2
9
F
AllNH2
MeO
10
F
4-MeOBnNC
1j
11
12
13
F
F
F
i-Bu
i-Pr
Et
AllNH2
AllNH2
AllNH2
CyNC
CyNC
t-BuNC
1k
1l
87
98
53
1m
MCPBA oxidizes primary and secondary amines to formed in toluene, a solvent more suited to the following
hydroxylamines at room temperature. Therefore, the steps. Before the addition of MCPBA, a small amount of
amine used as the nucleophile in the last step was added dichloromethane was introduced. Under these conditions,
in excess for prior decomposition of the unreacted perox- a sequential formation of 2,4-diaminopyrimidines with
ide. Three equivalents of morpholine were added to the
R2
former reaction mixture (in dichloromethane) but the sub-
stitution of the sulfone group was sluggish either at room
CONHR3
1) R1CHO + R2NH2 + R3NH2
toluene, 60 °C, 70 h
N
OH
temperature or under heating. However, heating the iso-
lated sulfone with the amine in refluxing toluene gave the
expected diaminopyrimidine in satisfactory yields. In or-
der to find a compromise for both steps, the sulfone for-
mation was performed in a 1:1 mixture of toluene and
dichloromethane. Under these conditions, the oxidation is
slightly longer but still high yielding (over 90%). After the
morpholine addition, the mixture was left at room temper-
ature for 20 minutes, and then refluxed with distillation of
the dichloromethane to afford the diaminopyridine 2a in a
74% isolated yield over two steps. A wide range of Ugi–
Smiles adducts behave similarly with primary and sec-
ondary amines as shown by the results displayed in
Table 2.
N
N
R1
N
N
2) CH2Cl2, MCPBA (3 equiv)
r.t., 5 h
3) NHR4R5 (3 equiv)
r.t., then 110 °C
N
S
Ph
R4
R5
N
CONHCy
N
CONHCy
N
N
i-Bu
N
N
Ph
HN
C6H4Cl
48%
HN
C6H4Cl
43%
N
CONHCy
N
N
Ph
N
O
Searching for an even simpler experimental protocol, a
one-pot version was tested starting directly from the S-
benzylthiouracil and using two different amines in the se-
quence. For this purpose, the Ugi–Smiles step was per-
46%
Scheme 2 One-pot synthesis of diaminopyrimidines
Synlett 2012, 23, 632–636
© Thieme Stuttgart · New York

634
M. A. Sidhoum et al.
LETTER
five points of diversity could be designed; albeit with strategy could be further applied to the formation of other
moderate yields (Scheme 2).
derivatives using carbon nucleophiles in place of the
amine; we are currently working towards this.
To conclude, we have disclosed a one-pot multicompo-
nent access to diaminopyrimidines. This methodology
opens the way to the preparation of libraries of pyrimidine
analogues related to DNA biosynthesis. This synthetic
Table 2 Synthesis of Diaminopyrimidines 2
R3
R3
N
CONHR4
1) MCPBA (3 equiv)
CH2Cl2–toluene (1:1)
r.t., 2 h
N
CONHR4
R2
N
N
R2
N
N
2) R5R6NH (3 equiv)
r.t., 20 min
then reflux, 7 h
S
N
R1
R5
R6
1
2
Entry
1
R5R6NH
Product
Yield (%)
N
CONHCy
N
N
Ph
1
1g
74
O
NH
N
O
2a
N
CONHCy
NH2
2
3
4
1g
1g
1l
57
68
74
N
N
Ph
C6H4Cl
Cl
HN
2b
N
CONHCy
O
N
N
Ph
O
NH2
HN
2c
N
CONHCy
i-Pr
C6H4Cl
NH2
N
N
Cl
HN
2d
N
CONHCy
i-Pr
N
N
5
1l
60
O
NH
N
O
2e
Synlett 2012, 23, 632–636
© Thieme Stuttgart · New York

LETTER
Multicomponent Access to 2,4-Diamino Pyrimidines
635
Table 2 Synthesis of Diaminopyrimidines 2 (continued)
R3
R3
N
CONHR4
1) MCPBA (3 equiv)
CH2Cl2–toluene (1:1)
r.t., 2 h
N
CONHR4
R2
N
N
R2
N
N
2) R5R6NH (3 equiv)
r.t., 20 min
then reflux, 7 h
S
N
R1
R5
R6
1
2
Entry
1
R5R6NH
Product
Yield (%)
MeO
O
C6H4Cl
N
N
H
NH2
NH2
NH2
6
7
1h
51
N
N
i-Bu
C6H4Cl
Cl
HN
HN
HN
2f
O
C6H4Cl
N
N
H
1a
1b
81
73
N
N
i-Bu
C6H4Cl
Cl
2g
O
N
NHCy
8
N
N
i-Bu
C6H4Cl
Cl
2h
Ugi–Smile Procedure for 1g
137–139 °C) in 74% isolated yield (322 mg). Rf = 0.3 (EtOAc–PE
= 40:60). 1H NMR (400 MHz, CDCl3): d = 7.94 (d, 1 H, J = 6.1 Hz,
H-12), 7.28–7.23 (m, 5 H, H-7, H-8, H-9), 6.14 (s, 1 H, H-2), 5.87
(d, 1 H, J = 6.1 Hz, H-11), 5.57–5.44 (m, 1 H, H-4), 4.98–4.90 (m,
2 H, H-5), 3.90–3.73 (m, 3 H, H-3, H-cy), 3.69–3.60 (m, 8 H, H-14,
H-15), 1.86–1.77 (m, 2 H, H-cy), 1.65–1.48 (m, 3 H, H-cy), 1.36–
1.21 (m, 2 H, H-cy), 1.12–0.90 (m, 3 H, H-cy). 13C NMR (100.6
MHz, CDCl3): d = 169.4 (C-1), 162.4 (C-10), 160.7 (C-13), 156.0
(C-12), 135.6 (C-6), 133.7 (C-4), 129.6 (C-7), 128.7 (C-8), 128.4
(C-9), 117.1 (C-5), 95.1 (C-11), 66.9 (C-15), 63.8 (C-2), 49.0 (C-3),
48.4 (C-cy), 44.4 (C-14), 33.2, 33.0 (C-cy), 25.5 (C-cy), 24.8, 24.7
(C-cy). HRMS: m/z calcd for C25H33N5O2: 435.2634; found:
435.2629. IR (thin film): 3309, 2932, 2850, 1658, 1239 cm–1.
To a 1 M solution of the benzaldehyde (1 mmol) in MeOH was suc-
cessively added allylamine (1 mmol), cyclohexylisocyanide (1
mmol), and 2-(benzylthio)pyrimidin-4-ol (1 mmol) under an inert
atmosphere. The resulting mixture was heated at 60 °C for 48 h. Af-
ter evaporation of the solvent, the mixture was purified by flash
chromatography to give 1g (340 mg, 72% yield) as a yellow solid
1
(mp 166–168 °C). Rf = 0.5 (EtOAc–PE = 60:40). H NMR (400
MHz, CDCl3): d = 7.91 (d, 1 H, J = 6.1 Hz, H-12), 7.30 (d, 2 H,
J = 7.1 Hz, H-16), 7.27–7.16 (m, 7 H, H-ar), 7.15–7.10 (m, 1 H, H-
ar), 6.30 (br s, 1 H, H-2), 6.10 (d, 1 H, J = 6.1 Hz, H-11), 5.79 (d, 1
H, J = 7.3 Hz, NH), 5.43–5.31 (m, 1 H, H-8), 4.88 (d, 1 H, J = 9.6
Hz, H-9), 4.86 (d, 1 H, J = 17.4 Hz, H-9), 4.29 (d, 1 H, J = 13.9 Hz,
H-14), 4.23 (d, 1 H, J = 13.9 Hz, H-14), 3.93–3.80 (m, 2 H, H-7),
3.75–3.64 (m, 1 H, H-cy), 1.84–1.71 (m, 2 H, H-cy), 1.60–1.44 (m,
3 H, H-cy), 1.29–1.15 (m, 2 H, H-cy), 1.06–0.89 (m, 3 H, H-cy). 13
C
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
NMR (100.6 MHz, CDCl3): d = 170.0 (C-13), 168.9 (C-1), 161.5
(C-10), 155.7 (C-12), 137.9 (C-15), 135.5 (C-3), 133.4 (C-8), 129.6
(C-ar), 128.8 (C-ar), 128.8 (C-ar), 128.5 (C-17), 128.5 (C-6), 127.1
(C-18), 116.9 (C-9), 100.7 (C-11), 62.2 (C-2), 48.7 (C-7), 48.6 (C-
cy), 35.2 (C-14), 32.9 (C-cy), 25.5 (C-cy), 24.9, 24.8 (C-cy).
HRMS: m/z calcd for C28H32N4OS: 472.2297; found: 472.2298. IR
(thin film): 3300, 2933, 1653, 1474, 1169 cm–1.
Acknowledgment
We thank ENSTA and CNRS for financial support.
References and Notes
Synthesis of Diaminopyridine 2a
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chromatography, compound 2a was obtained as a yellow solid (mp
© Thieme Stuttgart · New York
Synlett 2012, 23, 632–636

636
M. A. Sidhoum et al.
LETTER
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Synlett 2012, 23, 632–636
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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
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However, users may print, download, or email articles for individual use.