N-Heterocyclic carbene-catalyzed annulation of ynals with amidines: Access to 1,2,6-trisubstituted pyrimidin-4-ones

Article abstract of DOI:10.1039/c8cc02023j

An N-heterocyclic carbene-catalyzed annulation of ynals and amidines has been reported to construct pyrimidin-4-ones. The protocol features a broad substrate scope and mild conditions. Furthermore, an oxidative strategy to catalytically generate ynal-deri

Full text of DOI:10.1039/c8cc02023j

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N-Heterocyclic Carbene-catalyzed Annulation of Ynals
with Amidines: Access to 1,2,6-Trisubstituted
Pyrimidin-4-ones
Received 00th January 20xx,
Accepted 00th January 20xx
Yangxi Xie,a and Jian Wang,*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A N-heterocyclic carbene-catalyzed annulation of ynals and amidines has been reported to construct
pyrimidin-4-ones. The protocol features a broad substrate scope and mild conditions. Furthermore, an
oxidative strategy to catalytically generate ynal-derived acyl azolium intermediates is discussed in
mechanistic study.
(a) Representative molecules
Introduction
O
N
O
N
O
Pyrimidin-4-ones as pharmacophores are widely spread in natural
products and pharmaceuticals.1 As shown in Scheme 1a,
pyrimidin-4-ones have been found to be marketed medicines or
clinical candidates (e.g. HIV-1 inhibitor2a, COX inhibitor2b). Owing
to their broad range of medicinal properties, pyrimidin-4-ones
pave an avenue for synthetic chemists to explore their potential
applications in drug discovery.3 In the past decades, extensive
research has focused on the diversity-oriented synthesis4 of
Me
N
BnO
Ph
Me
Me
NH
N
NH
O
S
N
Ph
COXinhibitor
Phase II
pyrimidin-4-one
scaffold
HIV-1 inhibitor
(b) Previous work
Cl
R1
O
R1
O
pyrimidin-4-one
structures.
Two-component
condensation
O
O
O
Y
reaction is arguably one of the most straightforward and reliable
methods for their preparation.4a-d Pinner condensation of β-
ketoesters with non-substituted amidines is often used to
generate pyrimidinones (Scheme 1b (i)), but suffer from
competing O-alkylation byproducts in the late stage
R1
H
3
N
Y
R2
CO2X
R2
Cl
HN
NH
NH
5
5
(Y = H)
(ii)
(Y = H)
(i)
R3
N
R3
R1 R3
6 N 2
2
(c) This work
4c,
5
modification.4a,
Another alternative strategy is based on the
cat.
O
condensation of N-substituted amidines with malonyl dichlorides
R2
O
NHC
H
N
HN
NH
(Scheme 1b (ii)). However, it tolerates low yields, limited substrate
scope and highly reactive substrates malonyl dichlorides.4b,
+
H
6
2
1
N
4c
[O]
R1
R3
R3
R1
R2
Mild reaction condition
1,2,6-Trisubstituted
Broad scope
Taking into account the environmental and economic impacts,
therefore the development of catalytic strategies for pyrimidinone
synthesis has become a significant objective.
H
NH
N
O
Mes
R2
We herein report
a new and mild synthesis via the
condensation of ynals and amidines,6 catalyzed by N-heterocyclic
carbenes (NHCs). In contrast with previous methods, this protocol
yields 1,2,6-trisubstituted pyrimidin-4-ones with excellent
regioselectivity and also exhibits broad substrate scope and
[O]
N
R3
R1
S
Note:
most explored
rarely explored
OH
O
O
X
X
X
R
R
aSchool of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous
Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing,
100084, China
R
N
N
N
Y
Y
Y
Breslow
intermediate
ynal-derived
acyl azolium
Acyl azolium
intermediate
Scheme 1 Representative pyrimidin-4-ones and relevant synthetic
strategies.
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J. Name., 2013, 00, 1-3 | 1
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Sc(OTf)3, Mg(OTf)2) could enhance the performance of NHC
catalysis. Consequently, we envision that our reaction may
also be accelerated through such a similar activation mode.
Along with the addition of Mg(OTf)2, chemical yield of 3a was
significantly increased to 78% (entry 9). A switch of NaH to
Na2CO3 led to a slight increase in yield (entry 10, 87%). We
also noted that solvent has an effect on reaction conversion
functional group tolerance. NHC as versatile and powerful
organocatalysts have led substantial advances for the synthesis
of five- or six-membered heterocycles.7 Reported results have
indicated that NHC catalysts usually activate carbonyls to
generate a catalytic amount of NHC-bounded intermediates (e.g.
Breslow intermediate,8 homoenolate,9 or acyl azoliums10), which
will subsequently react with another counterpart to deliver target
molecules. Very recently, a rarely explored NHC-bounded ynal-
derived acyl azolium intermediate11 received an attractive
attention due to its potential applications in organic synthesis. For
example, our team successfully applied this acyl azolium
intermediate to NHC-catalyzed [3+3] atropo-enantioselective
annulation reaction.11b It is worth mentioning that triple bond in the
ynal-derived azolium intermediate would promise it to participate
in more transformations.
(entries 13-15). Eventually, a combination of catalyst
D (10
mol %), Na2CO3 (50 mol %), ratio of 1a 2a (1.5:1), and
:
toluene (1.0 mL) afforded product 3a in an excellent yield
(Table 1, entry 16, 92%).
Table 2 Scope of ynalsa
O
CHO
NH
cat. D (10 mol %)
N
O
Ph
DQ, Mg(OTf)2, Na2CO3
N
Ph
o
H
R
N
Ph
R
4A MS, toluene
N2, rt
Results and discussion
Table 1 Optimization of the reaction conditionsa
Ph
3
2a
1
O
O
N
N
N
N
Ph
Ph
Ph
N
Ph
N
Ph
Ph
Ph
Ph
F
MeO
Et
3b, 36 h, 89%
3c, 36 h, 94%
3d, 60 h, 67%
O
N
O
N
O
N
Me
Cl
N
N
Ph
N
Ph
Ph
Ph
Ph
Cl
Yield (%)b
trace
trace
trace
33
13
trace
52
3e, 60 h, 74%
3f, 48 h, 94%
3g, 60 h, 75%
Entry
1
2
3
4
5
6
7
8
Cat.
A
B
C
D
E
Additive
-
Base
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
-
-
-
-
O
N
O
O
N
N
CO2Me
N
N
Ph
N
Ph
F
-
Ph
Ph
O
Ph
D
D
D
D
D
D
D
D
D
D
Sc(OTf)3
Cu(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
43
78
87
68
22
23
18
3i, 60 h, 76%
3h, 48 h, 83%
3j, 60 h, 86%
9
NaH
10
11
12
13
14
15
16
Na2CO3
LiOt-Bu
Et3N
Na2CO3
Na2CO3
Na2CO3
Na2CO3
O
N
O
N
O
N
Et2O
CH2Cl2
toluene
R
N
Ph
N
Ph
N
Ph
16
Ph
3m (R = Me), 48 h, 71%b, c
3n (R = Et), 48 h, 62%b, c
92c
S
Ph
Ph
S
a
Reaction conditions: 1a (0.25 mmol), 2a (0.1 mmol), cat. A–F (10 mol
3k, 48 h, 97%
3l, 36 h, 96%
%), base (150 mol %), 3,3',5,5'-tetra-tert-butyldiphenoquinone (DQ) (0.2
mmol), additive (20 mol %), 4Å MS, solvent (1.0 mL), room temperature,
48 h. b Isolated yield after flash chromatograph. c 1a (0.15 mmol), Na2CO3
(50 mol %), DQ (0.12 mmol).
3o (R = n-C8H17), 48 h, 58%b, c
3p (R = cyclopropyl), 96 h, 67%b
a Reaction conditions: 1 (0.15 mmol), 2a (0.1 mmol), cat. D (10 mol %), Na2CO3
(0.05 mmol), DQ (0.12 mmol), Mg(OTf)2 (20 mol %), 4Å MS, toluene (1.0 mL), rt.
b 1 (0.25 mmol) and DQ (0.2 mmol) used. c 40oC used.
Our investigation began with ynal 1a (0.25 mmol) and
amidine 2a (0.1 mmol) as model substrates and 3,3',5,5'-
tetra-tert-butyldiphenoquinone (DQ) (0.2 mmol) as external
oxidant. Key results are briefly summarized in Table 1. A
screening of achiral NHC catalysts revealed that only
With the optimal reaction conditions in hand, we sought to
examine the scope of substrates. As indicated in Table 2, a
diverse set of electron-withdrawing (e.g. CO2Et) and electron-
donating (e.g. OMe, Et, Me) ynals were compatible with the
optimized conditions, thus resulting in the corresponding
pyrimidin-4-ones in good to high yields (3b−3h). It is noteworthy
that halides (e.g. F, Cl) in position 3 or 4 were also tolerated, and
the corresponding products (3d, 3e and 3g, respectively) could
thiazolium-derived catalyst
D and E could generate product
3a, but albeit with low chemical yields (Table 1, entries 4 and
5, 33% and 13%, respectively). Recently, the groups of
Scheidt,12 You,13 Chi14 and others15 reported that the addition
of Lewis acid (e.g. LiCl, Ti(OiPr)4, Mg(OtBu)2, NaBF4,
2 | J. Name., 2012, 00, 1-3
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undergo further cross-coupling reaction to make other useful replaced by naphthalene in amidine, the corresponding product
structures. When the phenyl ring was replaced by naphthalene or 4g was achieved in 79%. When R2 is occupied by an aromatic
heterocyclic ring in ynals, the corresponding products 3i−3l were ring, the corresponding pyrimidin-4-ones 4h−4m were observed in
still obtained in excellent yields. It is worth mentioning that this good yields. When alkyl groups appear in R2 position, amidines
method was compatible with β-alkyl enal, giving the still smoothly converted to desired products 4n−4p in moderate to
corresponding product 3m-p in an acceptable yield.
high yields. The configuration of 3a was determined by X-ray
single crystallography,16 and other products were assigned by
analogy.
Table 3 Scope of amidinesa
Scheme 2 Postulated mechanism
.
A postulated mechanism is depicted in Scheme 2. Ynal 1
reacts with NHC catalyst D to yield a NHC-bounded Breslow
intermediate I,8 and then undergoes an oxidation to produce
alkynyl acyl azolium intermediate II. In the presence of
magnesium(II),
N-substituted amidine 2 and alkynyl acyl azolium
II are both activated through coordination (see III). Michael
addtion allows III transfer to allenolate intermediate IV, and
subsequent proton transfer leads to intermediate V. Finally, an
intramolecular cycladdition of V delivers final product 3 and NHC
catalyst D is released for next catalytic cycle.
Conclusions
We have developed a new annulation reaction catalyzed
by a thiazolium carbene catalyst under mild conditions. The
catalytically
generated
ynal-derived
acyl
azolium
intermediates react with amidines, thus providing various
1,2,6-trisubstituted pyrimidin-4-ones in good to high yields.
Further investigations on both expansion of substrate scope
and developing novel catalytic reactions via the use of in situ-
generated ynal-derived acyl azolium intermediates are
currently underway in our laboratory.
a Reaction conditions: 1a (0.15 mmol), 2 (0.1 mmol), cat. D (10 mol %), Na2CO3
(0.05 mmol), DQ (0.12 mmol), Mg(OTf)2 (20 mol %), 4Å MS, toluene (1.0 mL), rt.
b 40 oC used.
We then turned our attention to explore the scope of amidine
components (Table 3). The steric and electronic effects of N-
monosubstituted amidines were evaluated systematically by
varying substituent patterns. No matter what phenyl group (R1)
bears electron-withdrawing or electron-donating group, good to
high yields were obtained regularly (4a−4f). When phenyl ring was
Acknowledgements
We acknowledge the National Natural Science Foundation of
China (21672121), the “Thousand Plan” Youth program of China,
the Tsinghua University, the Bayer Investigator fellow, the
fellowship of Tsinghua-Peking centre for life sciences (CLS) and
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1629.
16 CCDC
1811495
(
3a
)
contains
the
supplementary
Fang, T. Lu, J. D. Zhu, K. W. Sun, D. Du, Org. Lett. 2017, 19
,
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3470; For examples of NHC catalyzed annulations of ynals,
see: (i) B. Zhou, Z. Luo, Y. C. Li, Chem. Eur. J. 2013, 19, 4428;
(j) R. F. Han, J. Qi, J. X. Gu, D. H. Ma, X. G. Xie, X. G. She,
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8CC02023J
O
O
H
NH
[O]
N
+
HN
R2
R3
R1
N
R2
R3
R1
S
ClO4
N
28 examples
up to 97% yield
Mes
cat. NHC
A thiazolium-catalyzed annulation of ynals and amidines has been reported to construct
pyrimidin-4-ones.