Microwave assisted tandem heck-sonogashira reactions of N,N-Di-Boc-protected 6-amino-5-iodo-2-methyl pyrimidin-4-ol in an efficient approach to functionalized pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1021/ol501459e

A microwave assisted tandem Heck-Sonogashira cross-coupling reaction between 6-N,N-di-Boc-amino-5-iodo-2-methyl pyrimidin-4-ol and various aryl alkynyl substrates has been developed. This process generates novel 5-enynyl substituted pyrimidines, which can be transformed to novel functionalized pyrido[2,3-d]pyrimidines by way of a silver catalyzed cyclization reaction.

Full text of DOI:10.1021/ol501459e

Letter
pubs.acs.org/OrgLett
Microwave Assisted Tandem Heck−Sonogashira Reactions of N,N-Di-
Boc-Protected 6‑Amino-5-iodo-2-methyl Pyrimidin-4-ol in An
Efficient Approach to Functionalized Pyrido[2,3‑d]Pyrimidines
Yang Liu,† Shiyu Jin,† Zi Wang,‡ Linhua Song,‡ and Youhong Hu*,†
†State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi
Road, Shanghai, 201203, China
‡College of Science, China University of Petroleum (East China), Qingdao, 266580, China
S
* Supporting Information
ABSTRACT: A microwave assisted tandem Heck−Sonogashira cross-coupling reaction between 6-N,N-di-Boc-amino-5-iodo-2-
methyl pyrimidin-4-ol and various aryl alkynyl substrates has been developed. This process generates novel 5-enynyl substituted
pyrimidines, which can be transformed to novel functionalized pyrido[2,3-d]pyrimidines by way of a silver catalyzed cyclization
reaction.
yrido[2,3-d]pyrimidine is a core structure that is found in a
Scheme 1. Common Methods To Prepare Pyrido[2,3-
P
large variety of substances that exhibit important biological
d]pyrimidines
activities. For example, this heterocyclic structural motif is
present in AZD8055 (A), a selective ATP-competitive PI3K-
Akt-mTOR signaling pathway inhibitor used for the treatment
of antitumor,1 piritrexim (B), a lipid-soluble inhibitor of
dihydrofolate reductase (DHFR) that displays high potency
for the treatment of metastatic urothelial cancer,2 and
pyrido[2,3-d]pyrimidine derivative C that is a hepatitis C
virus replicon inhibitor3 (Figure 1). Also, substances that
possess the pyrido[2,3-d]pyrimidine framework have other
interesting biological properties such as anticardiovascular,4
anti-inflammatory,5 antibacterial,6,7and anti-Parkinson’s activ-
ities.8 The few methods thus far devised to prepare these
substances involve condensation reactions of pyridine or
pyrimidine9 (Scheme 1), which are only applied with difficulty
when diversified substitution patterns are required. Herein, we
describe a novel palladium catalyzed microwave-assisted
tandem Heck−Sonogashira reaction of 6-N,N-di-Boc-amino-5-
iodo-2-methylpyrimidin-4-ol with terminal alkynes (HCCR,
R = aryl group or TMS) that forms functionalized enyne
(−CC−CC−) substituted pyrimidines, which then under-
go cyclization to generate novel diverse substituted pyrido[2,3-
d]pyrimidines in good to excellent yields.
Scheme 2. Palladium Catalyzed Cross-Coupling of 2-
Substituted-6-amino-5-iodopyrimidin-4-ols
Palladium catalyzed Sonogashira reactions of 2-substituted-6-
amino-5-iodopyrimidin-4-ols (Scheme 2A) have been pre-
viously applied to the synthesis of functionalized heterocyclic
pyrimidines.10 However, the poor solubilities of 2-substituted-
Received: May 22, 2014
Published: June 23, 2014
Figure 1. Representative bioactive pyrido[2,3-d]pyrimidines.
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions for the
Formation of 5-Enynyl Substituted Pyrimidine 3aa
Table 2. Tandem Cross-Coupling Reactions of 1a with
a
a
Various Alkynes 2
d
yield (%)
entry
temp
Pd-catalyst
Pd(PPh3)4
base; solvent
3aa
4aa
1
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
60 °C
70 °C
90 °C
100 °C
80 °C
80 °C
DIPEA; MeCN
DIPEA; toluene
DIPEA; DMF
38
53
55
43
40
67
20
<5
40
20
17
10
15
18
5
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
Pd(OAc)2, PPh3
Pd/C, PPh3
Pd2(dba)3, PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
3
4
DIPEA; THF
5
Et3N; DMF
6
(n-Bu)3N; DMF
DABCO; DMF
DBU; DMF
7
40
45
32
8
9
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
(n-Bu)3N; DMF
10
11
12
13
14
15
16
trace
NR
NR
52
59
57
47
21
8
4
6
b
17
NR
c
18
71
<5
a
Unless otherwise noted, reactions were carried out under standard
b
c
conditions. The reactions were carried out without CuI. MW, 20
min. Yield of isolated product based on 1a.
d
6-amino-5-iodopyrimidin-4-ols limit applications of this ap-
proach. By taking into account the fact that the solubilities of
these substrates can be improved by introducing N,N-di-Boc
amine protecting groups, we have explored the use of the
protected aminopyrimidinol 1a in palladium catalyzed Sonoga-
shira cross-coupling reactions (Scheme 2B). Surprisingly, we
observed that 6-N,N-di-Boc-amino-5-iodo-2-methyl pyrimidin-
4-ol (1a) with ethynylbenzene 2a undergoes tandem Heck−
Sonogashira cross-coupling to form the unexpected and novel
5-enynyl substituted pyrimidine 3aa as the major product
(55%). In contrast, the expected Sonogashira cross-coupling
product 4aa is generated in this process in only a 10% yield. We
also found that catalytic silver trifluoroacetate in trifluoroacetic
acid promotes cyclization of 3aa to form the novel pyrido[2,3-
d]pyrimidine 5aa in high yield.
The tandem Heck−Sonogashira reaction of terminal alkynes
has been rarely described as a side reaction in the past.11 Only
few successful examples of this process, in which (thio)flavone,
thiophene, naphthalene, and benzene rings react with a limited
number of alkynes, have been reported.12
In the first phase of this effort, we examined the reaction of
1a with ethynylbenzene 2a using different conditions. The
results show that, among a variety of different solvents such as
acetonitrile, toluene, DMF, and THF (Table 1, entries 1−4),
DMF is superior for this reaction. In addition, an exploration of
different bases such as Et3N, (n-Bu)3N, DABCO, and DBU
(Table 1, entries 5−8) uncovered the observation that the weak
organic base (n-Bu)3N is more suitable for generation of enyne
3aa while the reaction using the strong organic base DBU
forms 4aa preferentially. Among the different catalysts explored
(Table 1, entries 9−12), the commonly used palladium catalyst
a
Unless otherwise noted, reactions were carried out under the
b
optimized conditions. Yields of isolated product based on 1a.
Pd(PPh3)4 is ideal and the reaction does not occur in the
absence of CuI as a cocatalyst (Table 1, entry17). Finally, in the
temperature range 60−100 °C (Table 1, entries 13−16), 80 °C
is more suitable for this process. Finally, when the reaction is
carried out under microwave irradiation at 80 °C for 20 min
(Table 1, entry 18) instead of oil-heating overnight, 3aa is
generated efficiently (71%) and highly selectively. In summary,
optimized conditions involve reaction in DMF at 80 °C for 20
min in the presence of 2.5 equiv of terminal alkyne, 4 equiv of
(n-Bu)3N, 0.05 equiv of Pd(PPh3)4, and 0.1 equiv of CuI under
microwave irradiation.
To explore the alkyne substrate scope of the tandem Heck−
Sonogashira process, various terminal alkynes 2 were reacted
with 1a using the optimized reaction conditions to generate 5-
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Organic Letters
Letter
Table 3. Tandem Cross-Coupling Reactions of 2f with o-
Iodo-N,N-di-Boc Aminoarenes 1
Table 4. Synthesis of Novel Functionalized Pyrido[2,3-
a
a
d]pyrimidines
a
Unless otherwise noted, reactions were carried out under standard
b
conditions. Yield of isolated product based on 1.
enynyl substituted pyrimidines 3 (Table 2). The results show
that alkynes containing electron-withdrawing and weak
electron-donating para-substituents on the aromatic ring react
to form enyne products in modest yields (Table 2, entries 2 and
3). However, in the reaction with the p-methoxyphenyl alkyne
2d was selective in that it produced 3ad along with the normal
Sonogashira coupling product 4ad (Table 2, entry 4).
Additionally, when the alkyne substituent is 2-thiophenyl
(Table 2, entry 5) and trimethylsilyl (Table 2, entry 6),
tandem processes occur to generate the respective enyne
products 3ae and 3af in moderate to high yields. However,
when the alkyne substrate possesses an alkyl substituent such as
the tert-butyl or n-butyl group, the reaction is complicated by
the production of a number of products, including those
formed by double-Heck and Sonogashira reactions (Table 2,
entries 7 and 8).
In a brief effort designed to probe the aryl iodide substrate
range of the tandem coupling process, alkyne 2f was reacted
with other o-iodo N,N-di-Boc-aminoarenes. The results
displayed in Table 3 show that tandem reactions of the 2-
phenyl-6-N,N-di-Bocamino-5-iodo-pyrimidin-4-ol 1b, pro-
tected-aminoiodobenzene 1c, and pyridines 1d−e, using
a
Unless otherwise noted, the reactions were carried out under
b
standard conditions. Yields of isolated products based on 3.
13
ZnBr2 in place of CuI as the cocatalyst and a higher
temperature of 100 °C, led to high yielding production of the
desired enyne products (Table 3, entries 1−4).
place at the terminal alkyne position, leading to generation of 2-
methyl-3-trimethylsilyl-pyridine-fused aromatic products
(Table 4, entries 5−9).
In order to demonstrate the importance of the novel tandem
Heck−Sonogashira coupling process, we have explored
cyclization reactions of the eneyne products promoted by
catalytic silver trifluoroacetate in trifluoroacetic acid. Nearly all
of the 5-enynyl substituted pyrimidines 3 and related benzene
and pyridines are efficiently transformed to the novel
substituted pyrido[2,3-d]pyrimidines 5 (Table 4 entries 1−9).
Surprisingly, treatment of 3ad under these conditions leads to
production of a complicated mixture of products. Interestingly,
under the cyclization reaction conditions desilylation takes
It is noteworthy that Boc protecting groups play an
important role in guiding the operation of the tandem
Heck−Sonogashira process. In the mechanistic route followed
in this reaction, arylpalladium species M1 is likely the first
intermediate generated by the oxidative addition of Pd (0)
species with the 5-iodo pyrimidine (Scheme 3). M1 undergoes
syn addition to the triple bond of the alkyne to provide the
crucial Pd−C σ-bonded vinylpalladium species M2, which
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Organic Letters
Letter
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could be stabilized by a carbonyl oxygen of the Boc protecting
group. Subsequent insertion into the second terminal alkyne
followed by reductive elimination then gives the enyne 3.
In conclusion, in the effort described above we have
developed a novel microwave-assisted tandem Heck−Sonoga-
shira reaction of 6-N,N-di-Boc-amino-5-iodo-2-methyl-
pyrimidin-4-ol that forms functionalized enyne (−CC−
CC−) substituted pyrimidines. The products of this process
undergo ready cyclization to generate novel substituted
pyrido[2,3-d]pyrimidines in good to excellent yields. Notably,
the enyne forming and cyclization sequence is applicable to the
synthesis of a variety of novel highly functionalized fused
pyridines. Further studies are underway to show that this
chemistry is applicable to the preparation of heterocycle
libraries for high throughput screening efforts.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectral data for all new compounds
and crystal structure data for 3af in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
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Cardenas, D. J.; Echavarren, A. M. J. Org. Chem. 1998, 63, 2854−2857.
(e) Stara,
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*E-mail: yhhu@mail.shcnc.ac.cn.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support of this research provided by the National
Natural Science Foundation of China (81225022) and SA-SIBS
Scholarship Program is gratefully acknowledged.
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