Decarboxylative cross-couplings of 2-aminopyrimidine-5-carboxylic acids

Article abstract of DOI:10.1016/j.tet.2018.05.018

Decarboxylative C–C cross-couplings of 2-aminopyrimidine-5-carboxylic acids under a Pd/Ag-based catalytic system opens a new platform for the introduction of diverse C5 substituents. The reaction methods proceeded efficiently with a wide range of the acids and the coupling partners of aryl iodides, alkenes, bromoalkynes, and azoles. Considering ready availability of 2-aminopyrimidine-5-carboxylic acid from the oxidative dehydrosulfurative C–N cross-coupling of the 3,4-dihydropyrimidin-1H-2-thiones, this reaction method unambiguously pave a shortcut to densely substituted 2-aminopyrimidine derivatives with unprecedented diversity.

Full text of DOI:10.1016/j.tet.2018.05.018

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Decarboxylative cross-couplings of 2-aminopyrimidine-5-carboxylic acids
Ngoc Son Le Pham, Jihong Lee, Hyunik Shin, Jeong-Hun Sohn
PII:
S0040-4020(18)30537-4
10.1016/j.tet.2018.05.018
TET 29525
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 March 2018
Revised Date: 2 May 2018
Accepted Date: 7 May 2018
Please cite this article as: Pham NSL, Lee J, Shin H, Sohn J-H, Decarboxylative cross-couplings of 2-
aminopyrimidine-5-carboxylic acids, Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.018.
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Decarboxylative Cross-Couplings of 2-
Aminopyrimidine-5-Carboxylic Acids
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Le Pham Noc Son,a Jihong Lee,a Hyunik Shinb and Jeong-Hun Sohn*a
aDepartment of Chemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764
Korea; bYonsung Fine Chemicals R&D Center, Suwon 443-380 Korea

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Tetrahedron
journal homepage: www.elsevier.com
Decarboxylative Cross-Couplings of 2-Aminopyrimidine-5-Carboxylic Acids
Ngoc Son Le Pham,a Jihong Lee,a Hyunik Shin,b and Jeong-Hun Sohn*a
aDepartment of Chemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764 Korea, bYonsung Fine Chemicals R&D Center, Suwon
443-380 Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Decarboxylative C-C cross-couplings of 2-aminopyrimidine-5-carboxylic acids under a Pd/Ag-
based catalytic system opens a new platform for the introduction of diverse C5 substituents. The
reaction methods proceeded efficiently with a wide range of the acids and the coupling partners
of aryl iodides, alkenes, bromoalkynes, and azoles. Considering ready availability of 2-
aminopyrimidine-5-carboxylic acid from the oxidative dehydrosulfurative C-N cross-coupling of
the 3,4-dihydropyrimidin-1H-2-thiones, this reaction method unambiguously pave a shortcut to
densely substituted 2-aminopyrimidine derivatives with unprecedented diversity.
Available online
Keywords:
decarboxylative coupling
arylation
2018 Elsevier Ltd. All rights reserved
.
olefination
alkynylation
pyrimidinecarboxylic acid
1. Introduction
substrates possessing diverse substituents at the C4 and C6
positions,7 this reaction method offers preparation of pyrimidine
derivatives with rapid diversification of C4 and C6 substituents,
and C2 amino groups. For final derivatization of the remaining
C5 position, at which substituents are usually alkoxycarbonyl
groups, we focused on decarboxylative C-C cross-coupling of 2-
aminopyrimidine-5-carboxylic acids 2 produced by the hydrolysis
of ester I.
As evidenced in the commercialized drugs such as the
hypocholesterolemic agent rosuvastatin (Crestor)1 and the potent
anticancer drug imatinib (Gleevec),2 the 2-aminopyrimidine
motifs have been recognized as important privileged substructure
in drug discovery area.3 (Figure 1). Its popularity could also be
observed in the development candidates, particularly in the
inhibition of protein kinases or receptors.4 Although their growing
biological importance requires facile access to highly
functionalized derivatives, the traditional synthetic route towards
this class of compounds usually suffers from multiple steps and
the limited substrate scope.5
R1
R1
CO2R2
R3
Biginelli
reaction
O
HN
CO2R2
R3
NH2
S
N
H
S
NH2
O
DHPM (1)
ref 6
R1
R1
N
R
CO2R2
This work
N
N
R'
R'
R3
N
R3
decarboxylative
C-C cross-coupling
N
N
R''
R''
I, R2 = alkyl
3
, R2 = H
R
= aryl, alkenyl, or alkynyl group
2
Scheme 1. Decarboxylative C-C cross-couplings of 2-
Figure 1. Structures of Rosuvastatin and imatinib.
aminopyrimidine-5-carboxylic acids
Recently, we reported the oxidative dehydrosulfurative C-N
cross-coupling of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs)
Transition metal-catalyzed decarboxylative cross-couplings
have emerged as powerful tools to provide regiospecific carbon-
carbon bond formation for target oriented synthesis.8 Successful
reactions of various aromatic carboxylates with a broad range of
coupling partners have been achieved.9,10 Five-membered
heteroaromatic systems, such as oxazole-, thiazole-, pyrrole-,
with
aryl-
and
alkylamines
to
produce
2-
aryl(alkyl)aminopyrimidine derivatives in a single-step under a
Pd/Cu catalytic system (Scheme 1).6 Since the well-known
Biginelli three-component reaction easily produces DHPM
Corresponding author. Tel.: +82-42-821-5479; fax: +82-42-821-8896; e-mail: sohnjh@cnu.ac.kr

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Tetrahedron
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thiopene-, and furancarboxylic acids, were also suitable for the
reaction.11 However, the couplings for π-deficient heteroaromatic
systems are very rare, especially for highly privileged scaffolds
such as pyrimidines.12 Herein, we report the decarboxylative C-C
cross-couplings of densely substituted 2-aminopyrimidine-5-
carboxylic acids with aryl iodides, alkenes, and bromoalkynes as
the coupling partners under a Pd/Ag-based catalytic system.
Implementation of this chemistry could offer a highly efficient
route for unprecedented diversification of 2-aminopyrimidines.
To achieve this regiospecific cross-coupling, it is necessary to
suppress the competitive protodecarboxylation reaction (Scheme
2).
H
N
side-product
R1HN
N
HX
Ar
X
[M]
N
L2Pd
CO2
O
R'RN
N
Ar-X
PdL2
N
O
[M]
R'RN
N
Ar
L2Pd
N
[M]X
HX
Ar
N
NRR'
N
CO2H
N
R'RN
N
R'RN
N
desired product
Scheme 2. Decarboxylative cross-coupling and the competitive
protodecarboxylation pathways of 2-aminopyrimidinecarboxylic
acid and aryl halide
2. Results and Discussion
The initial studies were decarboxylative arylation with acid 2a
and PhBr in the presence of PdCl2, CuO, and PPh3 in N-
methylpyrrolidone (NMP) at 130 °C for 12 h to produce the
desired decarboxylative arylation product 3a in 62% yield, along
with the protodecarboxylative product 3a’ (25%) (Scheme 3).
This result paved the way for further optimization studies.
Table 1. Decarboxylative arylationa,b
aReaction conditions; 1a, ArI (2 equiv), PdCl2 (5 mol%), PPh3 (10 mol%),
Ag2CO3 (3 equiv) and 4 Å MS in DMA under Ar at 155-160 °C for 16 h.
bIsolated yields.
With respect to the aryl iodide, a range of functional groups on
Ph and heteroaromatic ring were suitable for the reaction. First,
we performed the reaction with aryl iodides containing electron-
donating and withdrawing substituents to study the electronic
effects. Both substituents resulted in the desired products with
Scheme 3. Initial result of the decarboxylative arylation of 2a
Previous work on the decarboxylative arylations of thiazole- good yields. The m-methyl and p-methoxy groups afforded the
and oxazolecarboxylic acids with aryl halides by Greaney group desired products 3b and 3c in 79% and 72% yields, respectively.
provided some clue to optimal conditions.11b Further optimization
Halide groups F and Cl yielded the corresponding products 3d
was carried out by varying the reaction parameters including the (86%) and 3e (90%), respectively, in high yields. Br afforded 3f
Pd source, phosphine ligand, metal source, solvent, and in low yield, which may be attributed to a competitive side-
temperature. We obtained the desired product 3a in 86% yield
reaction. The F group at the ortho position afforded 3g in 79%
when 2a was reacted with PhI under the reaction conditions with yield. Other electron-withdrawing groups, such as NO2, CN,
PdCl2 (5 mol%), PPh3 (10 mol%), Ag2CO3 (3 equiv), and 4 Å CHO, and CF3 at the para position, also exhibited good yields in
molecular sieves in N,N-dimethylacetamide (DMA) at 155-160
the production of 3h-3k. No significant steric hindrance was
°C for 16 h. We investigated the scope of the reaction under observed for the o-Me group in the production of 3l (80%), while
optimal reaction conditions with various acid substrates and aryl very bulky 2,6-dimethyl groups afforded 3m in 33% yield.
iodides (Table 1).
Bicyclic 1-iodonaphthalene produced the desired product 3n in