Construction of Dihydropyrido[2,3- d]pyrimidine Scaffolds via Aza-Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes

Article abstract of DOI:10.1021/acs.joc.0c00657

N-Heterocyclic carbenes (NHCs) catalyzing aza-Claisen rearrangement of α,β-unsaturated enals with cyclic vinylogous amides under oxidative conditions generating potentially biologically active dihydropyridinone-fused uracils have been developed. This strategy represents a unique NHC-activation-based path with the use of 6-aminouracils as stable α,β-diEWG cyclic vinylogous amides for the efficient synthesis of bicyclic N-unprotected lactams similar to those in many useful drugs.

Full text of DOI:10.1021/acs.joc.0c00657

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Article
CONSTRUCTION OF DIHYDROPYRIDO[2,3-D]PYRIMIDINE
SCAFFOLDS VIA AZA-CLAISEN REARRANGEMENT
CATALYZED BY N-HETEROCYCLIC CARBENES
Krzysztof Dzieszkowski, Izabela Bara#ska, and Zbigniew Rafi#ski
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00657 • Publication Date (Web): 20 Apr 2020
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CONSTRUCTION OF DIHYDROPYRIDO[2,3-D]PYRIMIDINE SCAFFOLDS VIA
AZA-CLAISEN REARRANGEMENT CATALYZED BY N-HETEROCYCLIC CARBENES
Krzysztof Dzieszkowski,[a] Izabela Barańska[a] and Zbigniew Rafiński[a]*
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Dedication to Professor Grzegorz Mlostoń on the Occasion of his 70th Birthday.
Faculty of Chemistry
Nicolaus Copernicus University in Torun
7 Gagarin Street, 87-100 Torun, Poland
e-mail: payudo@chem.umk.pl
Abstract: N-Heterocyclic carbenes (NHC)
catalyzing aza-Claisen rearrangement of α,β-
unsaturated enals with cyclic vinylogous amides
under oxidative condition generating potentially
biologically active dihydropyridinone-fused
uracils have been developed. This strategy
represents an unique NHC-activation-based
path with the use of 6-aminouracils as stable
α,β-diEWG cyclic vinylogous amides for the
efficient synthesis of bicyclic N-unprotected
lactams similar to many useful drugs.
NHC-catalyzed reactions take place via normal
polarity intermediates have gained in importance.
There are four well-studied paths of generating α,β-
unsaturated acyl azoliums: the reaction of NHCs
with α,β-unsaturated enol esters or acyl fluorides,4
ynals,5 2-bromoenals6 or stoichiometric oxidation of
Breslow intermediates.7
O
O
HN
Me
N
N
Me
O
O
O
N
N
N
O
F
1. INTRODUCTION
HN
H
N
I
O
The
development
of
new
synthetic
N
methodologies for the efficient construction of
bioinspired targets constitutes a highly relevant and
rapidly developing field in the contemporary organic
chemistry.1 Among them, dihydropyridinones and
derivatives of bicyclic pyridinone-fused uracils
constitute privileged heterocyclic scaffolds found in
many natural active molecules displaying a wide
range of biological and pharmacological properties.
For instance, GSK1120212 1 and his analogues 2, 3
were found to be a highly potent and selective
Me
Me
Cl
1
2
O
O
Me
O
Me
NH
N
N
N
N
Me
O
HN
N
O
Me
O
inhibitor
of
mitogen-activated
protein
kinase/extracellular signal-regulated kinase kinase
(MEK) as a highly antiproliferative drug candidate
for clinical development. Structurally similar
dihydropyrido[2,3-d]pyrimidine 4 is commonly
investigated as safe and highly effective
antileishmanial pharmaceutical (Figure 1).2 In the
view of the therapeutic significance of these uracil
derivatives, the development of general and concise
synthetic strategies that fill the chemical space with
diverse heterocyclic structures is highly desirable.
Br
4
3
Figure 1. Importance of dihydropyridinone-fused uracil
structural motifs.
The reactions of α,β-unsaturated acyl azoliums with
nucleophiles are unique organocatalytic strategies
leading to annulative reactions with single, double
Consequently,
synthesis
of
new
bicyclic
and
even
triple
functionalization
via
dihydropyridinone-fused uracils gives hope to
discover novel biologically active compounds.
domino/cascade
processes.3d,8
NHC-catalyzed
annulations of acyl species with various N-protected
imine derivatives are well-recognized and provide
facile entry to diverse heterocyclic motifs.9
Therefore, many methods have been developed for
the construction of N-protected dihydropyridinones,
including reactions of various precursors of α,β-
unsaturated acyl azoliums derived from α-
N-Heterocyclic carbenes (NHC) have emerged as
versatile organocatalysts for various trans-
formations and constitute a convenient methods for
carbon-carbon and carbon-heteroatom bond
formation.3 In recent years, processes in which
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bromoenals or enals under oxidative conditions with
vinylogous amides, which to date, have not been
different
partners
such
and
as
used as substrates for Claisen rearrangement under
N-Ts-2-aminoacrylates,
cyclic
acyclic
oxidative conditions, introducing a new tool for the
synthesis of complex bicyclic molecules.
N-sulfonylimines.10 Very recently, Enders et. al.
disclosed the use of benzoxazolyl and benzothiozolyl
acetates as enamine precursors leading to the
Table 1. Optimization of the reaction conditions[a,b]
dihydrobenzoxazolyl-
dihydropyridinones
or
benzothiozolyl-fused
low-to-moderate
O
with
8a-f (10 mol%)
9
enantioselectivity.11 Bode have examined the ability
of β-electron-withdrawing substituted enamines to
the synthesis of useful dihydropyridinones from the
α,β-unsaturated acyl azoliums.12 In 2017, Ye utilized
indolin-2-imines as enamine precursors allowing the
base (20 mol%)
DQ (1 eq.)
N
N
O
O
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O
NH
N
N
solvent, rt, 20 h
O
O
NH2
MeO
MeO
7aaa
5a
6a
entry preNHC
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MTBE
base
yieldb (%)
54
synthesis
of
nonenantioselective
dihydropyridinone-fused
indoles.13
Another
1
2
8a
8b
8c
8d
8e
8f
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NMM
HMPA
tBuOK
AcOK
Cs2CO3
P2-Et
interesting approach for their synthesis was
application of azolium dienolate intermediates with
hydrazones as reported by Chi and coworkers.14 The
synthetic utility of the immediate annulation
products, however, is diminished by the use of
difficult to remove protecting group. Despite the
fact of dynamically developing catalysis involving
NHC’s during last few years, organocatalytic aza-
Claisen rearrangements are still rare, as the
reported reactions are strongly limited in scope. To
our knowledge, there is no organocatalytic
approach for the annulative one-pot strategy for
50
3
95
4
84
5
48
6
35
7
8c
8c
8c
8c
8c
8c
8c
8c
8c
8c
30
8
21
9
88
construction
of
bicyclic
N-unprotected
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11
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13
14
15
16
54
dihydropyrido[2,3-d]pyrimidine
derivatives
79
involving the use of sterically hindered α,β-diEWG
cyclic vinylogous amides as a template for uracil
functionalization (Scheme 1). Our literature survey
did not lead to any precedence, either metal- or
organo-catalyzed, on the synthesis 7. Consequently,
the development of an effective synthetic method
for 7, possibly metal-free and organocatalytic is
highly expected.
64
K3PO4
K3PO4
K3PO4
90
DCM
67
AcOEt
85
1,4-dioxane K3PO4
43
Ph
ClO4
ClO4
Mes
N
N
N
N
X
Cl
Mes
N
N
N
N
S
N
Ph
Mes
Ph
Ar
8a - Ar = Ph
8d
8e
8f
8b - Ar = C6F5
8c - Ar = Mes
tBu
tBu
tBu
O
O
tBu
DQ
[a] Unless otherwise noted, all reactions were carried out
with preNHC 8a-f (10 mol%), base (20 mol%), DQ (1.0 eq.),
5a
Scheme 1. Synthesis of bicyclic NH-heterocycles by NHC
(0.3 mmol), and 6a (0.3 mmol) in the solvent (3.0 mL) at rt
catalyzed annulation reaction.
for
20 h. [b] Isolated yield.
Given the significance of both the bicyclic
pyrido[2,3-d]pyrimidine derivatives and the acyl
azolium chemistry, the studies on the development
of a general synthetic strategy leading to the novel
dihydropyridinones bearing a fused uracil moiety
were undertaken. Herein, we report our results on
this NHC-catalyzed aza-Claisen rearrangement
leading to bicyclic dihydropyridinones. The reaction
reveals a new reactivity of stable α,β-diEWG cyclic
2. RESULTS AND DISCUSSION
We started the evaluation of our hypothesis by
combining 4-methoxycinnamaldehyde 5a with
1,3-disubstituted 6-aminouracil 6a using different
azolium salts as
a NHC precursors, tribasic
potassium phosphate as a base, and DQ as an
equimolar oxidant in toluene. To our great delight,
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O
8c (10 mol%)
K3PO4 (20 mol%)
DQ (1 eq)
all tested NHC precatalysts 8a-f displayed
2
3
O
R3
R2
(1)
N
(3)
N
O
R3
R2
N
N
remarkably effects on the outcome of the reaction
R1
and afforded the desired product in wide range of
yields (Table 1). Gratifyingly, the desired
dihydropyrido[2,3-d]-pyrimidine 7aaa could be
obtained in 95% yield when the precatalyst 8c was
employed (Table 1, entry 3). Encouraged by this
promising results, various reaction parameters were
further examined. All the tested organic and
inorganic bases, including NMM, HMPA, AcOK, gave
the desired product, albeit in low yields (entries 7, 8,
10). Interestingly, when the reaction was carried out
using bases, such as tert-BuOK, KHMDS, and tribasic
potassium phosphate the reactivity increased
significantly, and the results indicated that K3PO4
was the best choice and furnish the desired product
in 95% yield. Moreover, the change of solvents did
not improve the reaction performance and toluene
was proven to be the solvent of choice.
O
NH
4
5
6
7
8
9
toluene
rt, 20 h
O
NH2
R1
O
5
6
7
O
N
O
O
O
N
N
N
N
N
N
N
O
NH
O
NH
O
NH
O
NH
O
O
O
O
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11
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MeO
AcO
OMe
OMe
7aaa
95%
7baa
83%
7caa
79%
7daa
72%
O
N
O
O
O
N
N
N
N
N
N
N
O
NH
O
NH
O
NH
O
NH
O
O
O
O
Me
Cl
Br
F
7faa
77%
7haa
99%
7eaa
61%
7gaa
98%
O
O
O
O
N
N
N
N
N
N
N
N
O
NH
O
NH
O
NH
O
NH
Me
O
O
O
O
O
O2N
7iaa
65%
7jba
67%
7kba
66%
7lba
66%
O
N
O
O
O
N
N
N
N
N
N
N
O
NH
O
NH
O
NH
O
NH
O
O
O
O
3
4
2
7pba
55%
7mba
70%
7oba
60%
7nba
45%
O
N
O
O
O
N
N
N
N
N
N
N
N
O
NH
O
NH
O
NH
O
O
NH
O
O
O
6
7
7qba
46%
7rba
61%
7sba
67%
7tba
no reaction
O
O
N
N
N
N
O
NH
O
O
NH
O
MeO
MeO
7aac
56%
7aab
77%
Scheme 2. Scope of the α,β-unsaturated aldehydes and
N(3)-substituted of the 6-aminouracils.
With the optimized reaction condition in hand,
we set out to explore the generality of the
procedure in terms of substrates. Initially, a variety
of substituted cinnamaldehyde derived enals
including those bearing electron-withdrawing and
electron-donating substituents were explored under
the optimized conditions. As shown in Scheme 2,
a number of aryl-substituted cinnamaldehydes
reacted smoothly and cleanly afforded the
corresponding annulation products in high yields
(7aaa-7iaa). Notably, the extension of the protocol
to alkyl-substituted enals was also successful and
gave the desired dihydropyrido[2,3-d]pyrimidines in
good
yields
(7kba-sba).
Unfortunately,
(E)-3-dimethylaminoacrylaldehyde was unreactive
in this model reaction (7tba). It is worth noting, that
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O
8c (10 mol%)
K3PO4 (20 mol%)
DQ (1 eq)
aromatic substituents on the enals afforded the
R2
NH
O
R1
N
N
(1)
N
(3)
N
R3
R2
O
expected adducts in greater yield than the aliphatic
counterparts. Additionally, we also applied
modification in uracil moiety by replacing the alkyl
group in N(3) position with a benzyl substituent, in
order to make them visible during chromatographic
purification with a UV detector.
O
toluene
rt, 20 h
O
NH2
O
MeO
MeO
5a
6
7
O
O
O
O
N
N
N
N
N
N
N
N
O
NH
O
NH
O
NH
Encouraged by the above successful aza-Claisen
rearrangement, we decided to further increase the
attractiveness of the methodology by using
unsymmetrical N,N-disubstituted alkyl-alkyl, and
alkyl-aryl derived 6-aminouracils (Scheme 3). The
influence of the length of the alkyl group in N(3)
position was first investigated.
Pleasingly, linear or branched alkyl chain did not
affect the reaction outcome, and we were able to
isolate the products in good yields (7afd, 7aca-7aja).
Increasing steric hindrance at the N(1) position does
not affect the reaction efficiency (7abc, 7ajb). Alkyl
chains containing a aryl moieties with both electron-
poor and electron-rich substituents at various
positions of the aromatic ring were well tolerated,
and gave the desired adducts (7abb, 7alb-7aub). The
significant influence on the yield was observed for
p-substituted benzyl group (products 7anb and
7aub).
To demonstrate the scalability of this aza-Claisen
transformation, we also performed the reaction in
a 50-fold larger scale. Under the optimized reaction
condition, the annulation proceeded smoothly and
gave the bicyclic heterocycle in 57% yield (3.17 g)
(Scheme 4).
Furthermore, we also were interested in the
development of an enantioselective approach to the
synthesis of dihydropyridinone-fused uracils (Table
2). After extensive investigations, we found that the
chiral pinene-derived NHC precatalyst (8g)
developed by us gave the best results in terms of
enantioselectivity.15 Unfortunately, the introduction
of additives in the form of Lewis acids or Bronsted
acids did not have a positive effect on the increase
of enantiomeric excess (entries 8-14, Table 2).
O
NH
9
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
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MeO
MeO
MeO
MeO
7afd
77%
7aea
75%
7ada
61%
7aca
73%
O
O
O
O
N
N
N
N
N
N
N
N
2
3
4
O
NH
O
NH
O
NH
O
NH
O
O
O
O
MeO
MeO
MeO
MeO
7aha
74%
7aia
87%
7aja
69%
7aga
69%
O
N
O
N
O
N
O
N
N
N
N
N
O
NH
O
NH
O
NH
O
NH
O
O
O
O
MeO
MeO
MeO
MeO
7abc
72%
7ajb
58%
7aba
90%
7aka
79%
O
O
O
N
Me
O
Me
N
N
N
N
N
N
N
Me
O
NH
O
NH
O
NH
O
NH
O
O
O
O
MeO
MeO
MeO
MeO
7abb
80%
7alb
43%
7amb
43%
7anb
34%
O
O
F
O
MeO
N
N
N
O
N
N
N
Me
O
NH
NH
O
O
NH
O
Me
MeO
O
MeO
MeO
7aob
69%
7apb
77%
7aqb
62%
F
Br
F3C
O
O
O
N
O
N
N
N
O
N
N
N
N
O2N
NH
O
NH
NH
O
NH
O
O
O
O
O
MeO
MeO
MeO
MeO
7arb
75%
7asb
58%
7atb
87%
7aub
29%
Scheme 3. NHC-catalyzed aza-Claisen rearrangement:
N(1) and N(3) substituent variation.
O
8c (10 mol%)
K3PO4 20 mol%
N
N
O
O
O
NH
N
N
+
O
DQ (1 eq.)
toluene
rt, 20 h
MeO
O
NH2
MeO
7aaa
8.53 mmol, 3.17 g
57%
5a
15 mmol, 2.43 g
6a
15 mmol, 3.17 g
Scheme 4. Scale-up of the NHC-catalyzed aza-Claisen
rearrangement and enantioselective approach to the
synthesis of dihydropyrido[2,3-d]pyrimidine 7aaa.
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Table 2. Enantioselective Synthesis of Dihydropyridinone
rearrangement is followed by the intramolecular
2
3
7aaa [a,b]
lactamization and affords the dihydropyridinone-
fused uracil and catalyst turnover. Another
possibilities for this NHC-catalyzed annulation is
nucleophilic addition of uracil enamine to the
α,β-unsaturated acyl azolium intermediate as
a Michael acceptor in 1,4-fashion, providing the enol
intermediate VIII, which undergoes proton transfer
and intramolecular acylation to afford the final
product. One of the characteristic experimental
observations of 1,2-addition is the presence of
amidation side-reaction product. The occurrence of
this type of by-product depends on the construction
of the NHC catalyst. In our research, for selected
NHC catalysts, amidation side-reactions were also
observed, which indicates the course of the reaction
not via nucleophilic 1,4-addition of enamine to the
catalytically generated α,β-unsaturated acyl
azolium but proceed through 1,2-addition to give N-
acylation product. Intensive mechanistic and kinetic
investigations for α,β-unsaturated acyl azoliums
conducted by Bode group, confirmed that NHC-
catalyzed annulation reactions of α,β-unsaturated
4
5
6
O
8g-l (10 mol%)
K3PO4 (20 mol%)
DQ (1 eq.)
N
N
O
O
O
NH
N
N
7
8
toluene, rt, 24 h
O
O
NH2
MeO
MeO
7aaa
5a
6a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
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entry
preNH
C
additive
Yieldb (%)
ee
1
2
8g
8h
8i
----------
----------
----------
----------
----------
----------
----------
Sc(OTf)3
LiCl
84
76
86
78
43
67
49
---
38
13
---
38
43
45
O
67
38
30
16
36
22
30
---
3
4
8j
5
8k
8l
6
7
8m
8g
8g
8g
8g
8g
8g
8g
Me
8
acyl azoliums proceed through
a
Claisen
9
65
---
rearrangement rather than
a direct Michael
10
11
12
13
14
O
Ti(OPri)4
Mg(OTf)2
AcOH
addition.16 Based on theoretical and kinetic studies,
we have adopted the above reaction mechanism as
the most likely for our model reaction.5b,17
Moreover, it is worth noting that [3+3] cycloaddition
is rather typical for analogous aminocatalytic
reactions.18
---
67
67
67
Me
R-Phos
S-Phos
O
Me
N
N
N
N
N
O
N
N
N
N
O
Me
Me
N
N
Me
Me
Me
Cl
8h
Me
Cl
Ar
H
Cl
O
NH
8g
8i
Mes
Ar
O
N
N
Mes
O
Me
N
OH
N
Cl
N
N
N
O
Me
N
Mes
O
N
N
Me
N
N
Ar
I
N
HO
N
N
N
Me
O
N
Cl
Ar
[O]
Me
8l
Me
base
N
HN
Me
Ph
Me
N
II
Me
N
Cl
8j
8k
3
O
VII
Mes
O
N
N
BF
Mes
4 Me
Ar
N
N
O
N
N
N
O
Ar
O
O
O
O
O
N
P
P
III
N
N
N
H2N
Ph
O OH
Me
O OH
N
OTBS
Mes
N
Me
8m
Ar
O
NH2
N
HO
O
N
VI
O
N
-PHOS
S
-PHOS
R
N
HN
IV
Mes
Ar
N
N
HO
N
O
[a] Unless otherwise noted, all reactions were carried out
O
N
HN
N
N
with preNHC 8g-l (10 mol%), K3PO4 (20 mol%), DQ (1.0
V
O
eq.),
5a
Mes
Ar
N
(0.3 mmol), and 6a (0.3 mmol) in the toluene (3.0 mL) at rt
HO
N
OH
N
HN
N
for
N
O
24 h. [b] Isolated yield.
VIII
1,4-Michael addition
The proposed catalytic cycle is presented in
Scheme 5. First, the NHC organocatalyst I is
generated by deprotonation of the triazolium salt 8.
The nucleophilic addition of a free NHC I to the enal
gives the Breslow intermediate II which is oxidized
to form the key α,β-unsaturated acyl azolium III.
Afterward, the 1,2-addition of cyclic enamine to the
acyl azolium gives
obtained hemiaminal IV undergoes aza-Claisen
rearrangement via transition state V. This
Scheme 5. Proposed mechanism.
Finally, the versatile functionalization of the
dihydropyrido[2,3-d]pyrimidines was also carried
out (Scheme 6). Treating 7aaa with LiAlH4 led to the
N-acylation product. The
corresponding
tetrahydropyridine
9
motif.
Derivatization of N-H bond in the lactam motif gave
a series of highly interested results. The reaction of
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Page 6 of 23
1
2
7aaa with tosyl chloride in pyridine under mild
activation-based
approach
via
aza-Claisen
conditions afforded the pyridinium zwitterion 10 in
20% yield. The replacement of the pyridine with
Hünig base results in tosylation of the amide at the
oxygen of the carbonyl group, and aromatization of
the pyridinone framework. Equally intriguing results
were obtained using the benzylation reaction. It
turns out that depending on the benzyl halide used,
the reaction leads to two different products. The use
of benzyl bromide with potassium carbonate in DMF
at 80 °C under inert atmosphere leads to the
formation of an O-benzylated product 12 in 63%
yield. This effect can be explained by the large steric
hindrance at the nitrogen atom of the amide group.
Nevertheless, the replacement of bromide with
benzyl chloride under analogous reaction conditions
gives an O-benzylation product with simultaneous
aromatization of the pyridinone motif 13. The
impact of factors on aromatization have not yet
been fully understood. The influence of the chloride
anion may have a decisive role, but further intensive
research in this direction is needed.
rearrangement. Furthermore, the protocol also
allows an access to the structural units that are
difficult to prepare by traditional strategies. The
mild reaction conditions, the very broad reaction
scope, and the readily available substrates make this
protocol potentially useful for the construction of
dihydropyrido[2,3-d]pyrimidine derivatives in good
yields. This work contributes the first use of
6-aminouracils as a cyclic enamide templates, thus
demonstrating the possibility of this novel approach
to the design of biologically relevant molecules.
Further studies toward more sustainable synthesis
for condensed cyclic heterocycles are currently an
area of focus in our laboratory.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. EXPERIMENTAL SECTION
General information. Presented reactions were
carried out in dry glassware under inert atmosphere
of argon. Selected reactions were monitored using
thin-layer chromatography (TLC), which was
visualized under UV lamp (254 nm). Anhydrous
solvents were prepared using INERT PureSolv
Solvent Purification System. Purification of selected
O
products
was
performed
by
column
N
N
LiAlH4
chromatography using CombiFlash Rf+ Lumen
system with UV-VIS and ELSD detectors. RediSepRf
GOLD 4 gram columns were used. NMR spectra were
recorded on Bruker AMX 400 [400 MHz (1H)]
spectrometer and Bruker AMX 700 [700 MHz (1H)]
spectrometer, using CDCl3 and DMSO-d6 as solvents.
Chemical shifts are reported in ppm using the
residual solvent peaks as reference: CDCl3 (δ 7.24) or
O
NH
THF
rt, 24 h
9
72%
O
MeO
MeO
N
N
TsCl
O
N
pyridine
rt, 24 h
N
10
20%
1
DMSO-d6 (δ 2.54) for H NMR and relative to the
central CDCl3 (δ 77.23) or DMSO-d6 (δ 41.23)
resonance for 13C NMR. Coupling constants (J) was
provided in Hz. Infrared spectra were registered on
Alpha FT-IR spectrometer from Bruker with ATR
module. Mass spectra were recorded on Agilent
6530 Q-TOF LC/MS system coupled with 1290
Infinity II liquid chromatograph. Melting points of
obtained products were measured on Stuart SMP30
and SMP50 Melting Point Apparatus and were not
corrected.
O
O
N
N
N
N
TsCl, DIPEA
O
NH
O
N
DCM
rt, 24 h
O
OTs
MeO
11
35%
MeO
7aaa
O
N
N
BnBr, K2CO3
O
O
N
N
DMF
80 oC, 24 h
OBn
OBn
General procedure for the preparation of 1,3-
disubstituted 6-aminouracils
12
63%
O
MeO
MeO
N
N
BnCl, K2CO3
O
O
Step I
Step II
O
DMF
80 oC, 24 h
HN
NCCH2CO2Et
HN
DMF-DMA
DMF
R1
N
NH2
EtONa, EtOH
reflux, 72 h
O
N
N
N
O
N
R1
NH2
40 oC, 24 h
H
13
R1
45%
17-19
14-16
Step III
O
Step IV
O
R2
Scheme 6. The synthetic transformations of the product
R2
N
R2Cl or R2Br
N
NaOH
7aaa.
MeOH, H2O
rt, 24 h
K2CO3, DMF
80 oC, 24 h
O
N
NH2
O
N
R1
N
N
R1
20-43
44-48 & 50-68
3. CONCLUSIONS
Step I. General Procedure 1: Synthesis of 3-
Unprotected 6-Aminouracils. Sodium ethoxide
solution was prepared from sodium metal (2 eq) and
dry ethanol (2 M solution). To the resulting solution,
1-monosubstituted urea (1 eq) and ethyl
cyanoacetate (1 eq) were added. The flask with the
In summary, we have developed very efficient
methodology for the synthesis of bicyclic
dihydropyridinone-fused
uracils
from
1,3-disubstituted 6-aminouracils as a α,β-diEWG
cyclic vinylogous amide templates with various
α,β-unsaturated aldehydes using a unique NHC-
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resulting mixture was immersed in an oil bath and
3329, 3250, 3070, 2954, 2766, 1695, 1628, 1576, 1494,
2
heated under reflux for 72 hours. After this time, the
solvent was removed using rotary evaporator and
residual solid was dissolved in water. The obtained
alkaline solution was neutralized by hydrochloric
acid, precipitated solid was filtered off and washed
with water and diethyl ether. The obtained solid was
dried under vacuo (0.1 Torr, 2 hours).
Step II. General Procedure 2: Synthesis of NH2-
Protected 6-Aminouracils. To the solution of 3-
unprotected 6-aminouracil (1 eq) in DMF (0.6 M
solution) DMF-DMA (1.1 eq) was added. The flask
with the resulting mixture was immersed in an oil
bath and heated at 40 °C for 24 hours. After this time,
the solution was cooled down to room temperature
and diethyl ether was added. Precipitated solid was
filtered off and washed with diethyl ether. The
obtained product was dried under vacuum (0.1 Torr,
2 hours).
1401, 1385, 1358, 1278, 1232, 1175, 1124, 941, 891, 822,
729, 692, 592, 538, 510, 434 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C11H12N3O2 218.0930; Found: 218.0931;
mp 270.5-273.1 °C (dec.). The above analysis results
3
4
5
6
7
8
9
correspond to the literature data19b
.
6-Amino-1-phenylpyrimidine-2,4(1H,3H)-dione (16), 50
mmol scale, solid, 6.65 g, isolated yield 65%; 1H NMR (400
MHz, DMSO-d6) δ 10.48 (s, 1H), 7.45-7.57 (m, 3H), 7.27-
7.37 (m, 2H), 6.11 (s, 2H), 4.69 (s, 1H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 163.3, 156.1, 151.4, 134.6, 130.2,
129.9, 129.7, 75.5; IR νmax: 3476, 3331, 3086, 2971, 2798,
2776, 1705, 1623, 1583, 1472, 1430, 1384, 1296, 1222,
1144, 875. 804, 777, 761, 702, 566, 531, 510 cm-1; HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C10H10N3O2 204.0773;
Found: 204.0773; mp 321.9-323.7 °C (dec.). The above
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
analysis results correspond to the literature data19c
.
N'-(2,6-dioxo-3-propyl-1,2,3,6-tetrahydropyrimidin-4-yl)-
N,N-dimethylformimidamide (17), 30 mmol scale, solid,
5.48 g, isolated yield 81%; 1H NMR (700 MHz, DMSO-d6) δ
10.58 (s, 1H), 8.05 (s, 1H), 4.96 (s, 1H), 3.81 (t, J = 7.4 Hz,
2H), 3.10 (s, 3H), 2.97 (s, 3H), 1.52 (sxt, J = 7.4 Hz, 2H),
0.82 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6)
δ 163.3, 160.6, 155.9, 151.7, 82.3, 42.8, 40.3, 34.4, 21.6,
11.2; IR νmax: 3152, 3016, 2965, 1659, 1627, 1557, 1445,
1421, 1395, 1356, 1331, 1230, 1111, 865, 604, 535, 432
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C10H17N4O2
225.1352; Found: 225.1350; mp 217.6-220.7 °C. The
above analysis results correspond to the literature
Step III. General Procedure 3: Synthesis of 1,3-
Disubstituted NH2-Protected 6-Aminouracils. NH2-
protected 6-aminouracil (1 eq) was dispersed in
DMF (0.3 M solution) and potassium carbonate
(2 eq) was added. The corresponding alkyl or benzyl
halide was added (10 eq) and the flask with the
resulting mixture was immersed in an oil bath and
heated at 80 °C for 24 hours. The majority of solvent
and unreacted halide was evaporated. To the
residue water was added and precipitated solid was
filtered off and washed with diethyl ether. The
obtained product was dried in vacuo (0.1 Torr; 2
hours).
data19d
.
Step IV. General Procedure 4: Synthesis of 1,3-
Disubstituted 6-Aminouracils
N'-(3-benzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-
N,N-dimethylformimidamide (18), 48.7 mmol scale, solid,
10.84 g, isolated yield 82%; 1H NMR (400 MHz, DMSO-d6)
δ 8.07 (s, 1H), 7.19-7.33 (m, 5H), 5.10 (s, 2H), 5.04 (s, 1H),
3.09 (s, 3H), 2.94 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-
d6) δ 163.7, 160.8, 156.5, 152.3, 139.0, 128.7, 127.6,
127.3, 82.6, 44.7, 40.8, 35.0; IR νmax: 2976, 2784, 1694,
1646. 1611, 1549, 1491. 1452, 1427, 1389, 1329, 1256,
1215, 1152, 1121, 1088, 1060, 1019, 904, 876, 813, 787,
760, 741, 701, 600, 583, 516, 462, 431 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C14H17N4O2 273.1352; Found:
273.1351; mp 221.7-223.4 °C. The above analysis results
1,3-Disubstituted NH2-protected 6-aminouracil (1
eq) was dissolved in methanol (0.2 M solution). To
the resulting solution 2 M sodium hydroxide
solution (2 eq) in water was added . The resulting
mixture was stirred at room temperature for 24
hours. After this time methanol was evaporated and
water was added. The resulting mixture was stirred
at 0 °C for 1 hour. Precipitated product was filtered
off and washed with water and diethyl ether.
Obtained solid was dried under vacuum (0.1 Torr; 2
hours).
6-Amino-1-propylpyrimidine-2,4(1H,3H)-dione (14), 50
mmol scale, solid, 5.97 g, isolated yield 71%; 1H NMR (400
MHz, DMSO-d6) δ 10.27 (s, 1H), 6.78 (s, 2H), 4.53 (s, 1H),
3.68 (t, J = 7.6 Hz, 2H), 1.51 (sxt, J = 7.5 Hz, 2H), 0.86 (t, J
= 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.9,
156.2, 151.7, 75.7, 42.6, 21.3, 11.2; IR νmax: 3363, 3190,
2962, 1705, 1651, 1574, 1502, 1463, 1386, 1280, 1223,
1170, 1072, 1025, 851, 774, 726, 702, 649, 539, 519, 465
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C7H12N3O2
170.0930; Found: 170.0928; mp 259.3-262.3 °C. The
above analysis results correspond to the literature
correspond to the literature data19d
.
N'-(2,6-dioxo-3-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)-
N,N-dimethylformimidamide (19), 24.2 mmol scale, solid,
5.54 g; isolated yield 89%; 1H NMR (700 MHz, DMSO-d6) δ
10.79 (s, 1H), 7.96 (s, 1H), 7.36-7.40 (m, 2H), 7.30-7.34 (m,
1H), 7.14-7.17 (m, 2H), 5.09 (d, J = 1.9 Hz, 1H), 2.98 (s, 3H),
2.51 (s, 2H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 163.6,
161.0, 155.2, 151.5, 137.1, 129.5, 128.2, 127.5, 82.3, 40.1,
33.9; IR νmax: 2963, 2808, 1698, 1650, 1615, 1541, 1446,
1425, 1373, 1337, 1261, 1210, 1130, 1087, 879, 787, 736,
698, 588, 568, 532, 458, 424 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C13H15N4O2 259.1195; Found: 259.1196;
mp 276.1-279.0 °C. The above analysis results correspond
data19a
.
6-Amino-1-benzylpyrimidine-2,4(1H,3H)-dione (15), 57.3
1
mmol scale, solid, 10.71 g, isolated yield 86%; H NMR
to the literature data19d
.
(400 MHz, DMSO-d6) δ 10.41 (m, 1H), 7.34 (m, 2H), 7.26
(m, 1H), 7.21 (m, 2H), 6.82 (s, 2H), 5.04 (s, 2H), 4.61 (s,
4H); 13C NMR{1H} (101 MHz, DMSO-d6) δ 162.8, 156.3,
152.0, 137.1, 128.9, 127.6, 126.8, 76.0, 44.0; IR νmax: 3471,
N'-(3-benzyl-2,6-dioxo-1-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (20), 21
mmol scale, used halide: iodide, solid, 4.86 g, isolated
1
yield 74%; H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H),
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2
3
4
5
6
7
8
7.18-7.33 (m, 7H), 5.18 (s, 1H), 5.16 (s, 2H), 3.73 (t, J = 7.3
2932, 2874, 1685, 1611, 1566, 1441, 1412, 1364, 1346,
Hz, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 1.51 (sxt, J = 7.4 Hz, 3H),
0.83 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6)
δ 162.5, 159.2, 156.5, 152.4, 138.9, 128.7, 127.6, 127.3,
82.2, 45.6, 42.0, 40.8, 35.0, 21.2, 11.6; IR νmax: 2961, 1690,
1648, 1618, 1569, 1496, 1448, 1414, 1363, 1224, 1125,
1096, 996, 810, 765, 693, 602, 577, 524 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C17H23N4O2 315.1821; Found:
315.1821; mp 130.2-132.8 °C. The above analysis results
1323, 1226, 1114, 1056, 992, 888, 806, 767, 577, 550 cm-
1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C14H25N4O2
281.1978; Found: 281.1980; mp 133.5-136.7 °C.
N'-(2,6-dioxo-1-pentyl-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (25), 4.46
mmol scale, used halide: bromide, solid, 1.00 g, isolated
1
9
yield 76%; H NMR (700 MHz, DMSO-d6) ) δ 8.07 (s, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.10 (s, 1H), 3.87 (t, J = 7.5 Hz, 2H), 3.72 (t, J = 1.0 Hz, 2H),
3.10 (s, 3H), 2.97 (s, 3H), 1.50-1.56 (m, 2H), 1.47 (dt, J =
15.0, 7.4 Hz, 2H), 1.23-1.30 (m, 4H), 0.80-0.85 (m, 6H);
13C{1H} NMR (176 MHz, DMSO-d6) δ 162.1, 159.0, 156.0,
151.7, 81.8, 67.4, 43.7, 40.3, 34.4, 28.6, 27.1, 21.9, 21.5,
13.9, 11.2; IR νmax: 2956, 2925, 2871, 1691, 1643, 1613,
1566, 1449, 1415, 1501, 1367, 1349, 1258, 1112, 1053,
994, 885, 807, 767, 728, 577, 553, 437 cm-1. HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C15H27N4O2 295.2134; Found:
295.2134; mp 80.1-86.9 °C.
correspond to the literature data19d
.
N'-(2,6-dioxo-3-phenyl-1-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (21), 19.3
mmol scale, used halide: iodide, solid, 3.17 g, isolated
1
yield 55%; H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H),
7.37-7.40 (m, 3H), 7.18 (dd, J = 3.7, 1.5 Hz, 2H), 5.25 (s,
1H), 3.74 (t, J = 7.3 Hz, 2H), 2.99 (s, 6H), 1.54 (sxt, J = 7.4
Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 162.9, 159.8, 155.6, 152.1, 137.9, 129.9,
129.8, 128.7, 82.2, 42.0, 34.3, 21.3, 11.7; IR νmax: 2953,
1696, 1651, 1612, 1572, 1424, 1406, 1375, 1341, 1116,
1079, 1005, 877, 798, 764, 700, 577, 536 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C16H21N4O2 301.1665; Found:
301.1662; mp 183.7-186.7 °C. The above analysis results
N'-(1-hexyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (26), 4.46
mmol scale, used halide: bromide, solid, 0.39 g, isolated
1
yield 28%; H NMR (700 MHz, DMSO-d6) δ 8.07 (s, 1H),
5.10 (s, 1H), 3.86 - 3.90 (m, 2H), 3.71 - 3.74 (m, 2H), 3.10
(s, 3H), 2.98 (s, 3H), 1.51-1.56 (m, 2H), 1.45-1.47 (m, 2H),
1.27-1.32 (m, 6 H), 0.81-0.85 (m, 6H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 162.5, 159.4, 156.3, 152.1, 82.3, 44.1,
correspond to the literature data19d
.
N'-(1-ethyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (22), 4.46
mmol scale, used halide: iodide, solid, 0.35 g, isolated
34.8, 31.4, 31.1, 27.8, 26.5, 22.4, 21.9, 14.3, 11.5; IR νmax
:
1
yield 31%; H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H),
3448, 3292, 3171, 2955, 2927, 1693, 1646, 1614, 1569,
1451, 1417, 1354, 1280, 1235, 1184, 1112, 1054, 999,
942, 887, 813, 789, 727, 717, 694, 555 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C16H29N4O2 309.2291; Found:
309.2294; mp 95.5-99.3 °C.
5.11 (s, 1H), 3.85-3.93 (m, 2H), 3.79 (q, J = 6.9 Hz, 2H),
3.11 (s, 3H), 2.99 (s, 3H), 1.49-1.61 (m, 2H), 1.06 (t, J = 7.1
Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 162.3, 159.4, 156.3, 151.9, 82.3, 44.1, 40.7,
35.4, 34.8, 21.9, 13.5, 11.5; IR νmax: 3088, 2965, 2934,
2875, 1687, 1648, 1614, 1566, 1448, 1416, 1362, 1337,
1233, 1116, 1037, 1001, 887, 815, 767, 666, 571, 551 cm-
1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C12H21N4O2
253.1665; found: 253.1666; mp 142.0-144.3 °C.
N'-(1-heptyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (27), 4.46
mmol scale, used halide: bromide, solid, 0.61 g, isolated
1
yield 42%; H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H),
5.10 (s, 1H), 3.11 (s, 3H), 2.99 (s, 2H), 1.51-1.58 (m, 2H),
1.44-1.51 (m, 2H), 1.26-1.31 (m, 8H), 0.81-0.86 (m, 6H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.4, 156.3,
152.2, 82.3, 44.1, 34.8, 31.7, 28.6, 27.9, 26.8, 22.5, 21.9,
14.4, 11.6; IR νmax: 2954, 2926, 2857, 1692, 1641, 1618,
1573, 1456, 1416, 1366, 1347, 1260, 1224, 1112, 1060,
993, 888, 807, 766, 572, 549 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C17H31N4O2 323.2447; found: 323.2446;
mp 70.0-75.9 °C.
N'-(1-butyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (23), 4.46
mmol scale, used halide: bromide, solid, 0.36 g, isolated
1
yield 29%; H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H),
5.11 (s, 1H), 3.85-3.93 (m, 2H), 3.75 (t, J = 7.1 Hz, 2H), 3.11
(s, 3H), 2.99 (s, 3H), 1.42-1.61 (m, 4H), 1.25 (dq, J = 14.9,
7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.4, 156.4,
152.1, 82.3, 44.1, 40.7, 34.8, 30.1, 21.9, 20.1, 14.2, 11.6;
IR νmax: 2960, 2932, 2873, 1687, 1645, 1611, 1568, 1494,
1439, 1412, 1365, 1348, 1226, 1181, 1112, 1048, 987,
886, 815, 766, 572, 550 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C14H25N4O2 281.1978; Found: 281.1977; mp
129.0-130.2 °C.
N'-(1-allyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (28), 4.46
mmol scale, used halide: bromide, solid, 0.36 g, isolated
1
yield 31%; H NMR (700 MHz, DMSO-d6) δ 8.09 (s, 1H),
5.79 (ddt, J = 17.2, 10.3, 5.2 Hz, 1H), 5.13 (s, 1H), 5.04 (dd,
J = 10.3, 1.3 Hz, 1H), 4.99 (dd, J = 17.2, 1.5 Hz, 1H), 4.35
(d, J = 5.2 Hz, 2H), 3.88 (t, J = 7.3 Hz, 2H), 3.11 (s, 3H), 2.98
(s, 3H), 1.54 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (176 MHz, DMSO-d6) δ 161.8, 159.2, 156.1,
151.5, 133.4, 115.8, 81.7, 43.8, 42.0, 40.4, 34.4, 21.5,
11.2; IR νmax: 2961, 2932, 2874, 1686, 1617, 1570, 1446,
1418, 1366, 1229, 1116, 994, 811, 767, 552 cm-1; HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C13H21N4O2 265.1665;
Found: 265.1663; mp: 151.1-153.0 °C.
N'-(1-isobutyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (24), 4.46
mmol scale, used halide: bromide, solid, 0.74 g, isolated
1
yield 59%; H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H),
5.11 (s, 1H), 3.90 (t, J = 7.2 Hz, 2H), 3.60 (d, J = 7.3 Hz, 2H),
3.11 (s, 3H), 2.99 (s, 3H), 2.00 (dt, J = 13.8, 6.9 Hz, 1H),
1.55 (sxt, J = 7.3 Hz, 2 H), 0.79-0.85 (m, 9H), 13C{1H} NMR
(101 MHz, DMSO-d6) δ 162.8, 159.34, 156.4, 152.4, 82.2,
47.2, 44.1, 40.7, 34.8, 27.1, 21.9, 20.4, 11.5; IR νmax: 2961,
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The Journal of Organic Chemistry
N,N-dimethyl-N'-(1-(2-methylallyl)-2,6-dioxo-3-propyl-
1,2,3,6-tetrahydropyrimidin-4-yl)formimidamide (29),
NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.17-7.35 (m,
2
3
10H), 5.26 (s, 1H), 5.17 (s, 2H), 4.97 (s, 2H), 3.10 (s, 3H),
2.95 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.4,
159.5, 156.7, 152.5, 138.8, 138.4, 128.7, 128.7, 127.8,
127.6, 127.3, 82.1, 45.8, 43.6, 40.8, 35.0; IR νmax: 2965,
2934, 2875, 1687, 1613, 1567, 1448, 1415, 1362, 1338,
1233, 1116, 1001, 815, 767, 570, 551 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C21H23N4O2 363.1821; Found:
363.1820; mp: 142.3-143.4 °C. The above analysis results
4
5
4.46 mmol scale, used halide: chloride, solid, 0.96 g,
isolated yield 77%; H NMR (400 MHz, DMSO-d6) δ 8.10
1
6
7
8
9
(s, 1H), 5.14 (s, 1H), 4.68 - 4.74 (m, 1H), 4.46 (s, 1H), 4.28
(s, 2H), 3.90 (t, J = 7.9 Hz, 2H), 3.12 (s, 3H), 3.00 (s, 3H),
1.67 (s, 3H), 1.55 (dq, J = 14.8, 7.4 Hz, 2H), 0.82 (t, J = 7.5
Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 159.6,
156.4, 152.0, 141.0, 109.2, 82.0, 45.1, 44.1, 34.8, 21.9,
20.8, 11.5; IR νmax: 3088, 2961, 2934, 2875, 1688, 1645,
1609, 1566, 1497, 1443, 1418, 1393, 1360, 1335, 1322,
1227, 1261, 1281, 1204, 1182, 1115, 1067, 1017, 993,
904, 881, 806, 764, 583, 552, 423 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C14H23N4O2 2279.1821; Found:
279.1822; mp 87.4-90.3 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
correspond to the literature data19e
.
N'-(3-benzyl-1-(2-methylbenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (34),
3.8 mmol scale, used halide: chloride, solid, 1.25 g, 91%;
1H NMR (700 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.19-7.30 (m,
6H), 7.04-7.12 (m, 2H), 6.77 (s, 1H), 5.29 (s, 1H), 5.17 (s,
2H), 4.93 (s, 2H), 3.10 (s, 3H), 2.95 (s, 2H), 2.32 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.6, 156.7,
152.5, 138.8, 136.1, 135.4, 130.3, 128.7, 127.5, 127.3,
N'-(1-benzyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (30), 7 mmol
scale, used halide: chloride, solid, 1.78 g, 81% yield; H
1
NMR (700 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.26-7.29 (m,
2H), 7.19-7.24 (m, 3H), 5.18 (s, 1H), 4.94 (s, 2H), 3.87-3.90
(m, 2H), 3.11 (s, 3H), 2.99 (s, 1H), 1.54 (sxt, J = 7.4 Hz, 2H),
0.82 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6)
δ 162.1, 159.3, 156.1, 151.8, 138.2, 128.3, 127.4, 126.9,
81.7, 43.9, 43.1, 40.4, 34.4, 21.5, 11.2; IR νmax: 2964, 2927,
2870, 1747, 1687, 1640, 1608, 1561, 1497, 1451, 1420,
1349, 1321, 1257, 1226, 1181, 1113, 1062, 1030, 989,
922, 885, 815. 691, 552 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C17H23N4O2 315.1821; Found: 315.1820; mp
116.6-118.1 °C.
126.8, 126.2, 124.9, 82.1, 45.8, 41.4, 35.0, 19.2 IR νmax:
3030, 2955, 2922, 1694, 1642, 1615, 1562, 1492, 1448,
1423, 1368, 1324, 1258, 1215, 1125, 1094, 998, 903, 813,
759, 741, 694, 603, 574, 525, 475 cm-1. HRMS (ESI-TOF):
(M+H)+ Calcd for C22H25N4O2 377.1978; Found: 377.1980;
mp 139.4-142.7 °C.
N'-(3-benzyl-1-(3-methylbenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (35),
3.8 mmol scale, used halide: chloride, solid, 0.74 g,
1
isolated yield 54%; H NMR (700 MHz, DMSO-d6) δ 8.12
(s, 1H), 7.26-7.30 (m, 2H), 7.19-7.25 (m, 3H), 7.13-7.18 (m,
1H), 6.99-7.04 (m, 3H), 5.24 (s, 1H), 5.16 (s, 2H), 4.92 (s,
2H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR
(176 MHz, DMSO-d6) δ 162.0, 159.0, 156.3, 152.1, 138.4,
138.0, 137.3, 128.3, 128.2, 127.8, 127.6, 127.2, 127.0,
124.4, 81.7, 45.3, 43.2, 40.5, 34.6, 21.1; IR νmax: 3061,
3032, 2925, 1692, 1621, 1562, 1490, 1446, 1423, 1386,
1364, 1337, 1280, 1254, 1210, 1128, 1094, 1067, 1015,
919, 899, 792, 764, 699, 597, 570, 522, 468 cm-1; HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C22H25N4O2 377.1978;
Found: 377.1978; mp 131.9-133.2 °C.
N'-(1-benzyl-2,6-dioxo-3-phenyl-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (31), 1.6
mmol scale, used halide: chloride, solid, 0.37 g, isolated
1
yield 65%; H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H),
7.17-7.42 (m, 10H), 5.32 (s, 1H), 4.98 (s, 2H), 3.00 (s, 3H),
2.53 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8,
160.0, 155.8, 152.2, 138.4, 137.8, 129.8, 128.7, 128.0,
128.0, 127.4, 82.1, 43.7, 34.3; IR νmax: 2917, 2951, 1695,
1652, 1613, 1591, 1569, 1490, 1416, 1398, 1377, 1352,
1332, 1302, 1266, 1233, 1137, 1102, 1072, 1060, 1025,
998, 947, 890, 808, 778, 744, 731, 711, 694, 574, 531, 468
cm-1; HRMS (ESI-TOF) m/z: (M+H): Calcd for C20H21N4O2
349.1665; Found: 349.1668; mp 158.2-164.2 °C.
N'-(1-allyl-3-benzyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-yl)-N,N-dimethylformimidamide (32), 3.8
mmol scale, used halide: bromide, solid, 1.10 g, isolated
yield 96%; H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H),
7.20-7.30 (m, 5H), 5.81 (ddt, J = 17.2, 10.4, 5.1, 5.1 Hz,
1H), 5.21 (s, 1H), 5.16 (s, 2H), 5.04 (dq, J = 2.9, 1.6 Hz, 1H),
4.37 (dt, J = 5.1, 1.5 Hz, 2H), 3.95 (d, J = 7.3 Hz, 1H), 3.09
(s, 3H), 2.94 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
162.2, 159.4, 156.6, 152.2, 138.8, 133.7, 128.7, 127.6,
127.3, 116.3, 82.0, 45.7, 42.5, 40.8, 35.0; IR νmax: 3080,
3033, 2946, 1689, 1649, 1613, 1567, 1494, 1443, 1417,
1391, 1365, 1323, 1257, 1210, 1122, 1093, 993, 925, 900,
818, 765, 740, 692, 642, 601, 523, 565 cm-1; HRMS (ESI-
TOF) m/z: (M+H): Calcd for C17H21N4O2 313.1665; Found:
313.1664; mp 135.0-138.5 °C.
N'-(3-benzyl-1-(4-methylbenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (36),
3.8 mmol scale, used halide: chloride, solid, 1.00 g,
1
isolated yield 72%; H NMR (400 MHz, DMSO-d6) δ 8.12
(s, 1H), 7.19-7.34 (m, 5H), 7.05-7.17 (m, 4H), 5.25 (s, 1H),
5.16 (s, 2H), 4.92 (s, 2H), 3.09 (s, 3H), 2.95 (s, 3H), 2.25 (s,
3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.4, 159.4,
156.7, 152.5, 138.8, 136.4, 135.4, 129.2, 128.7, 127.9,
1
127.6, 127.3, 82.1, 45.7, 43.4, 40.8, 35.0, 21.1; IR νmax
:
2965, 2934, 2875, 1688, 1614, 1566, 1448, 1416, 1363,
1233, 1117, 1001, 814, 767, 570, 551 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C22H25N4O2 377.1978; found:
377.1977; mp 156.6-159.7 °C.
N'-(3-benzyl-1-(4-isopropylbenzyl)-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide
(37), 3.8 mmol scale, used halide: chloride, solid, 1.47 g,
1
isolated yield 99%; H NMR (400 MHz, DMSO-d6) δ 8.12
(s, 1H), 7.26 (spt, J = 7.1 Hz, 6H), 7.16 (d, J = 1.2 Hz, 3H),
5.25 (s, 1H), 5.16 (s, 2H), 4.93 (s, 2H), 3.09 (s, 3H), 2.95 (s,
3H), 2.82 (s, 1H), 1.17 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101
MHz, DMSO-d6) δ/ppm = 162.4, 159.4, 156.7, 152.5,
N'-(1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
yl)-N,N-dimethylformimidamide (33), 3.8 mmol scale,
used halide: chloride, solid, 0.88 g, isolated yied 66%; 1H
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2
147.5, 138.8, 135.8, 133.6, 128.7, 127.9, 127.6, 126.6,
128.4, 127.1, 127.0, 126.6, 121.6, 81.6, 45.4, 42.7, 40.5;
82.1, 45.8, 43.4, 40.8, 35.0, 33.6, 24.4; IR νmax: 2957, 1694,
1638, 1610, 1560, 1510, 1445, 1421, 1407, 1356, 1346,
1295, 1256, 1216, 1125, 1092, 1056, 910, 899, 805, 768,
738, 698, 600, 589, 523cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C24H29N4O2 405.2291; Found: 405.2294. mp:
129.2-130.6 °C.
IR νmax: 2961, 1691, 1643, 1618, 1567, 1495, 1443, 1412,
1354, 1315, 1258, 1220, 1128, 1096, 1066, 987, 926, 842,
803, 765, 692, 613, 602, 520, 459 cm-1. HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C21H22BrN4O2 441.0926; Found:
441.0928. mp: 182.5-185.1 °C.
3
4
5
6
7
8
9
N'-(3-benzyl-2,6-dioxo-1-(3-(trifluoromethyl)benzyl)-
1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylform-
imidamide (42), 3.8 mmol scale, used halide: chloride,
solid, 1.17 g, isolated yield 74%; 1H NMR (700 MHz,
DMSO-d6) δ 8.14 (s, 1H), 7.60 (s, 1H), 7.55 (m, 3H), 7.19-
7.29 (m, 5H), 5.28 (s, 1H), 5.17 (s, 2H), 5.05 (s, 2H), 3.09
(s, 3H), 2.94 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
162.3, 159.6, 156.8, 152.5, 139.9, 138.7, 132.0, 129.9,
129.5 (q, J = 31.8 Hz), 128.7, 127.5, 127.4, 124.0 - 124.3
(m), 82.0, 45.8, 43.3, 40.9, 35.0; IR νmax: 2962, 1692, 1643,
1619, 1566, 1445, 1415, 1365, 1320, 1196, 1145, 1114,
1095, 1071, 990, 923, 889, 807, 768, 702, 695, 661, 601,
521 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C22H22F3N4O2 431.1695; Found: 431.1694; mp 188.6-
191.7 °C.
N'-(3-benzyl-1-(3-methoxybenzyl)-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide
(38), 3.8 mmol scale, used halide: chloride, solid, 0.80 g,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
isolated yield 56%; H NMR (400 MHz, DMSO-d6) δ 8.14
(s, 1H), 7.17-7.32 (m, 6H), 6.75-6.84 (m, 3H), 5.26 (s, 1H),
5.18 (s, 2H), 4.95 (s, 2H), 3.70 (s, 3H), 3.10 (s, 3H), 2.96 (s,
3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.4, 159.7,
159.5, 156.7, 152.5, 140.0, 138.8, 129.7, 128.7, 127.6,
127.3, 119.8, 113.4, 112.6, 82.1, 55.4, 45.7, 43.6, 40.8,
35.0; IR νmax: 2928, 2832, 1690, 1614, 1561, 1487, 1449,
1425, 1408, 1367, 1335, 1283, 1250, 1211, 1150, 1123,
1092, 1055, 921, 897, 805, 764, 699, 599, 571, 522, 476
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C22H25N4O3
393.1927; Found: 393.1927; mp 122.5-123.5 °C.
N'-(3-benzyl-1-(2-fluorobenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (39),
3.8 mmol scale, used halide: chloride, solid, 0.86 g,
isolated yield 61%; 1H NMR (700 MHz, DMSO-d6) ) δ 8.14-
8.16 (m, 1H), 7.25-7.30 (m, 3H), 7.19-7.25 (m, 3H), 7.14-
7.18 (m, 1H), 7.08-7.12 (m, 1H), 6.98-7.02 (m, 1H), 5.28 (s,
1H), 5.16 (s, 2H), 5.02 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H);
13C{1H} NMR (176 MHz, DMSO-d6) δ 161.9, 160.6, 159.2,
156.4, 152.0, 138.3, 128.7 (d, J = 8.2 Hz), 128.3, 127.8 (d,
J = 4.1 Hz), 127.2, 127.0, 124.7 (d, J = 14.3 Hz), 124.4 (d, J
= 3.3 Hz), 115.2 (d, J = 21.3 Hz), 81.6, 45.4, 40.5, 37.2 (d, J
= 5.3 Hz), 34.6; IR νmax: 1693, 1645, 1614, 1579, 1560,
1490, 1441, 1421, 1360, 1327, 1218, 1125, 1093, 813,
756, 701, 600, 524, 427 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C21H22FN4O2 381.1727; Found: 381.1725; mp
113.0-116.0 °C.
N'-(3-benzyl-1-(4-nitrobenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (43),
3.8 mmol scale, used halide: chloride, solid, 1.27 g,
1
isolated yield 85%; H NMR (400 MHz, DMSO-d6) δ 8.14-
8.20 (m, 3H), 7.49 (d, J = 8.8 Hz, 2H), 7.20-7.32 (m, 5H),
5.30 (s, 1H), 5.17 (s, 2H), 5.09 (s, 2H), 3.11 (s, 3H), 2.96 (s,
3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 159.7,
156.8, 152.5, 147.0, 146.4, 138.7, 128.8, 127.6, 127.4,
124.2, 124.0, 81.9, 45.9, 43.4, 40.9, 35.0; IR νmax: 1695,
1644, 1621, 1562, 1515, 1447, 1424, 1367, 1339, 1221,
1129, 1096, 990, 901, 856, 809, 765, 750, 692, 603, 577,
524 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C21H22N5O4 408.1672; Found: 408.1670; mp 176.8-182.7
°C.
6-amino-1-benzyl-3-propylpyrimidine-2,4(1H,3H)-dione
(44), 12.7 mmol scale, solid, 2.89 g, isolated yield 88%; 1H
NMR (400 MHz, DMSO-d6) δ 7.31-7.38 (m, 2H), 7.23-7.30
(m, 1H), 7.16-7.22 (m, 2H), 6.73-6.83 (m, 2H), 5.04-5.11
(m, 2H), 4.72 (s, 1H), 3.69 (t, J = 7.1 Hz, 2H), 1.49 (sxt, J=7.3
Hz, 2H), 0.82 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (176 MHz,
DMSO-d6) δ 161.4, 154.5, 151.6, 136.6, 128.5, 127.2,
126.4, 75.4, 44.6, 41.5, 20.9, 11.2; IR νmax: 3405, 3341,
3194, 2963, 1633, 1582, 1490, 1451, 1432, 1405, 1366,
1274, 1218, 1125, 1083, 809, 721, 685, 548, 517, 459 cm-
1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C14H18N3O2
260.1399; Found: 260.1400; mp 198.5-199.9 °C. The
N'-(3-benzyl-1-(3-fluorobenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (40),
3.8 mmol scale, used halide: chloride, solid, 0.99 g,
1
isolated yield 71%; H NMR (400 MHz, DMSO-d6) δ 8.14
(s, 1H), 7.19-7.38 (m, 6H), 6.99-7.11 (m, 3H), 5.27 (s, 1H),
5.17 (s, 2H), 4.98 (s, 2H), 3.10 (s, 3H), 2.96 (s, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 163.8, 162.3, 159.6, 156.8,
152.5, 141.4 (d, J=7.2 Hz), 138.8, 130.7 (d, J=7.9 Hz),
128.7, 127.6, 127.4, 123.8 (d, J=2.4 Hz), 114.5 (d, J=21.5
Hz), 114.2 (d, J=20.7 Hz), 82.0, 45.8, 43.3, 40.9, 35.0; IR
νmax: 1699, 1646, 1614, 1568, 1447, 1415, 1365, 1323,
1246, 1219, 1135, 1093, 985, 941, 878, 811, 765, 691,
603, 525, 465 cm-1; HRMS (ESI-TOF) m/z: (M+H): Calcd for
C21H22FN4O2 381.1727; Found: 381.1726; mp 135.8-141.6
°C.
above analysis results correspond to the literature data19f
.
6-amino-1-phenyl-3-propylpyrimidine-2,4(1H,3H)-dione
(45), 9.8 mmol scale, solid, 1.07 g, isolated yield 45%; 1H
NMR (700 MHz, DMSO-d6) δ 7.46-7.54 (m, 3H), 7.29-7.34
(m, 2H), 6.10 (s, 2H), 4.79 (s, 1H), 3.66 (t, J = 7.3 Hz, 2H),
1.49 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 162.1, 154.6, 151.6, 135.0,
130.1, 129.8, 129.7, 75.3, 41.8, 21.4, 11.7; IR νmax: 3342,
3531, 3176, 2972, 1694, 1663, 1612, 1587, 1477, 1437,
1404, 1359, 1453, 1299, 1154, 1101, 1064, 1019, 797,
761, 695, 573, 534 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C13H16N3O2 246.1243; Found: 246.1243; mp
N'-(3-benzyl-1-(3-bromobenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-N,N-dimethylformimidamide (41),
3.8 mmol scale, used halide: chloride, solid, 1.53 g,
1
isolated yield 94%; H NMR (700 MHz, DMSO-d6) δ 8.13
(s, 1H), 7.41-7.44 (m, 1H), 7.37-7.39 (m, 1H), 7.19-7.30 (m,
7H), 5.26 (s, 1H), 5.16 (s, 2H), 4.95 (s, 2H), 3.09 (s, 3H),
2.94 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.9,
159.2, 156.4, 152.0, 140.8, 138.3, 130.6, 130.0, 129.9,
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187.7-189.5 °C. The above analysis results correspond to
0.82-0.89 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
2
3
the literature data19g
.
161.7, 154.7, 151.8, 75.6, 43.5, 29.0, 27.6, 22.3, 21.3,
14.3, 11.2; IR νmax: 3439, 3352, 3117, 2959, 2930, 1646,
1603, 1500, 1456, 1411, 1368, 1271, 1191, 1113, 1048,
790, 769, 547 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C12H22N3O2 240.1712; Found: 240.1715; mp 92.2-95.5 °C.
6-amino-3-hexyl-1-propylpyrimidine-2,4(1H,3H)-dione
(51), 1.3 mmol scale, solid, 0.17 g, isolated yield 53%; 1H
NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.64 (s, 1H),
3.65-3.77 (m, 4H), 1.38-1.61 (m, 4H), 1.24 (s, 6H), 0.81-
0.89 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.7,
154.7, 151.8, 75.5, 43.5, 31.4, 27.9, 26.5, 22.4, 21.3, 14.3,
11.2; IR νmax: 3439, 3118, 2962, 2931, 1650, 1603, 1500,
1410, 1370, 1270, 1192, 788, 759, 545 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C13H24N3O2 254.1869; Found:
254.1868; mp 89.9-92.5 °C.
4
5
6
7
8
9
6-amino-3-ethyl-1-propylpyrimidine-2,4(1H,3H)-dione
(46), 1.3 mmol scale, solid, 70 mg, isolated yield 28%; 1H
NMR (400 MHz, DMSO-d6) δ 6.77 (s, 2H), 4.65 (s, 1H),
3.69-3.79 (m, 4H), 1.53 (sxt, J = 7.5 Hz, 2H), 1.02 (t, J = 7.0
Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 161.5, 154.7, 151.6, 75.6, 43.5, 40.7, 35.2,
21.3, 13.7; IR νmax: 3459, 3356, 3131, 2966, 2934, 2875,
1688, 1612, 1569, 1494, 1451, 1410, 1363, 1269, 1117,
1095, 787, 695, 593, 533 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C9H16N3O2 198.1243; Found: 198.1242;
mp 78.7-83.5 °C. The above analysis results correspond to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the literature data19h
.
6-amino-3-butyl-1-propylpyrimidine-2,4(1H,3H)-dione
(47), 1.3 mmol scale, solid, 0.12 g, isolated yield 41%; 1H
NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.65 (s, 1H),
3.65-3.78 (m, 4H), 1.53 (sxt, J = 7.5 Hz, 4H), 1.43 (quin, J =
7.4 Hz, 3H), 1.23 (dq, J = 14.9, 7.4 Hz, 6H), 0.81-0.91 (m,
6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.7, 154.7,
6-amino-3-heptyl-1-propylpyrimidine-2,4(1H,3H)-dione
(52), 1.9 mmol scale, solid, 0.15 g, isolated yield 29%; 1H
NMR (700 MHz, DMSO-d6) δ 6.77 (s, 2H), 4.63 (s, 1H), 3.72
(t, J = 7.7 Hz, 2H), 3.67 (d, J = 7.3 Hz, 2H), 1.51 (sxt, J = 7.5
Hz, 2H), 1.43 (quin, J = 7.4 Hz, 2H), 1.17-1.28 (m, 8H), 0.84
(td, J = 7.2, 2.6 Hz, 6H); 13C{1H} NMR (176 MHz, DMSO-d6)
δ 161.3, 154.3, 151.4, 75.1, 43.1, 31.3, 28.5, 27.6, 26.4,
22.1, 20.9, 14.0, 10.8; IR νmax: 3438, 3138, 2961, 2928,
2855, 1651, 1603, 1501, 1462, 1436, 1410, 1367, 1270,
1192, 1085, 789, 762, 544 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C14H26N3O2 268.2025; Found: 268.2022;
mp 71.2-75.2 °C.
151.8, 75.5, 43.5, 30.2, 21.3, 20.1, 14.2, 11.2; IR νmax
:
3437, 3114, 2962, 2931, 2874, 1698, 1654, 1604, 1503,
1464, 1436, 1411, 1364, 1284, 1270, 1198, 1180, 1044,
788, 760, 526 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C11H20N3O2 226.1556; Found: 226.1554; mp 91.4-98.1 °C.
6-amino-3-isobutyl-1-propylpyrimidine-2,4(1H,3H)-dione
(48), 2.6 mmol scale, solid, 0.21 g, isolated yield 36%; 1H
NMR (700 MHz, DMSO-d6) δ 6.77 (s, 2H), 4.64 (s, 1H), 3.73
(t, J = 1.0 Hz, 2H), 3.54 (d, J = 7.3 Hz, 2H), 1.95 (dquin, J =
13.8, 6.9, 6.9, 6.9, 6.9 Hz, 1H), 1.51 (sxt, J = 7.4 Hz, 2H),
0.84 (t, J = 7.4 Hz, 3H), 0.78 (d, J = 6.7 Hz, 6H); 13C{1H} NMR
(176 MHz, DMSO-d6) δ 161.6, 154.3, 151.7, 75.1, 46.6,
43.1, 26.7, 20.9, 20.0, 10.8; IR νmax: 3436, 3113, 2962,
1656, 1604, 1504, 1463, 1435, 1408, 1386, 1271, 1170,
1101, 1047, 788, 757, 548, 537 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C11H20N3O2 226.1556; Found: 226.1556;
mp 107.9-110.8 °C.
6-amino-1,3-dibutylpyrimidine-2,4(1H,3H)-dione (49)
1,3-dibutylurea (11.61 mmol; 2.00 g) and cyanoacetic acid
(12,77 mmol; 1.09 g) was dissolved in acetic anhydride
(12 mL). The resulting mixture was heating at 70 °C for 16
hours. After this time acetic anhydride was evaporated to
give a red viscous oil. The residue was dissolved in NaOH
solution in water (15 mL; 20%). Precipitated solid was
filtered off, washed with water (3 x 10 mL) and diethyl
ether (3 x 10 mL) and dried in vacuo (0.1 Torr, 2 hours).
Expected product (2.31 g) was obtained with 83% yield;
1H NMR (700 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.64 (s, 1H),
3.75 (t, J = 7.7 Hz, 2H), 3.68 (t, J = 7.3 Hz, 2H), 1.44-1.49
(m, 2H), 1.39-1.44 (m, 2H), 1.19-1.30 (m, 4H), 0.84-0.89
(m, 6H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.3, 154.3,
3-allyl-6-amino-1-propylpyrimidine-2,4(1H,3H)-dione
(53), 1.4 mmol scale, solid, 0.13 g, isolated yield 46%; 1H
NMR (400 MHz, DMSO-d6) δ 6.83 (s, 2H), 5.78 (ddt, J =
17.1, 10.3, 5.2, 5.2 Hz, 1H), 4.94-5.06 (m, 2H), 4.67 (s, 1H),
4.31 (d, J = 5.1 Hz, 1H), 3.74 (t, J = 7.8 Hz, 2H), 1.53 (dq, J
= 15.0, 7.5 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 161.3, 154.9, 151.6, 134.1, 116.0, 75.3,
43.6, 42.2, 21.2, 11.2; IR νmax: 3452, 3355, 3116, 2969,
1694, 1605, 1498, 1403, 1424, 1323, 1295, 1270, 1189,
1081, 1047, 994, 938, 776, 744, 669, 634, 546, 502, 463,
408 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C10H16N3O2 210.1243; Found: 210.1244; mp: 97.9-103.9
°C.
6-amino-3-(2-methylallyl)-1-propylpyrimidine-
2,4(1H,3H)-dione (54), 3.4 mmol scale, solid, 0.37 g,
isolated yield 48%; H NMR (700 MHz, DMSO-d6) δ 6.84
1
(s, 2H), 4.67-4.68 (m, 1H), 4.66 (s, 1H), 4.43 (dd, J = 1.6,
1.0 Hz, 1H), 4.21 (s, 2H), 3.73 (t, J = 1.0 Hz, 2H), 1.64 (d, J
= 0.4 Hz, 3H), 1.52 (sxt, J = 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.0, 154.5,
151.2, 140.8, 108.6, 74.8, 44.4, 43.2, 20.9, 20.4, 10.8; IR
νmax: 3438, 3114, 2974, 1653, 1604, 1502, 1423, 1398,
1294, 1270, 1194, 1096, 886, 779, 746, 567, 543 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C11H18N3O2
224.1399; Found: 224.1400; mp 93.0-97.0 °C.
151.3, 75.2, 41.6, 29.8, 29.7, 19.7, 19.3, 13.8, 13.8; IR νmax
:
3434, 3125, 2957, 2931, 2873, 1656, 1604, 1505, 1460,
1411, 1289, 790, 770, 530 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C12H22N3O2 240.1712; Found: 240.1710;
mp 96.5-102.2 °C.
6-amino-3-pentyl-1-propylpyrimidine-2,4(1H,3H)-dione
(50), 3.4 mmol scale, solid, 0.53 g, isolated yield 65%; 1H
NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.65 (s, 1H),
3.65-3.77 (m, 4H), 1.41-1.58 (m, 4H), 1.17-1.32 (m, 4H),
6-amino-3-benzyl-1-propylpyrimidine-2,4(1H,3H)-dione
(55), 4.6 mmol scale, solid, 1.01 g, isolated yield 84%; 1H
NMR (700 MHz, DMSO-d6) δ 7.24-7.28 (m, 2H), 7.18-7.23
(m, 3H), 6.88 (s, 2H), 4.89 (s, 2H), 4.70 (s, 1H), 3.70-3.75
(m, 2H), 1.51 (sxt, J = 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (176 MHz, DMSO-d6) δ 161.2, 154.6, 151.5,
138.4, 128.2, 127.4, 126.8, 74.9, 43.3, 43.0, 20.9, 10.8; IR
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2
νmax: 3479, 3067, 2964, 2876, 1688, 1646, 1607, 1583,
MHz, DMSO-d6) δ 161.2, 154.7, 151.7, 138.2, 137.3,
1490, 1453, 1428, 1402, 1343, 1288, 1258, 1190, 926,
897, 784, 757, 730, 700, 672, 646, 600, 547, 511 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C14H18N3O2
260.1399; Found: 260.1397; mp 147.3-151.9 °C.
136.6, 128.5, 128.2, 127.7, 127.5, 127.2, 126.4, 124.4,
75.2, 44.7, 43.0, 21.1; IR νmax: 3466, 3437, 3146, 1702,
1642, 1604, 1494, 1452, 1426, 1402, 1282, 936, 790, 757,
727, 689, 589, 535, 527, 464, 427 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C19H20N3O2 322.1556; Found:
322.1556; mp 90.0-93.2 °C.
3
4
5
6
7
8
9
6-amino-3-benzyl-1-phenylpyrimidine-2,4(1H,3H)-dione
1
(56) 1.1 mmol scale, solid, 0.24 g, isolated yield 77%; H
NMR (400 MHz, DMSO-d6) δ 7.48-7.56 (m, 3H), 7.20-7.37
(m, 7H), 6.22 (s, 2H), 4.93 (s, 2H), 4.89 (s, 1H); 13C{1H} NMR
(101 MHz, DMSO-d6) δ 162.1, 154.9, 151.8, 138.6, 134.8,
130.2, 129.8, 128.6, 128.0, 127.3, 75.2, 43.4; IR νmax: 3449,
3293, 3229, 3178, 1702, 1635, 1610, 1578, 1469, 1450,
1421, 1397, 1350, 1287, 1182, 1153, 1077, 1049, 1021,
942, 789, 772, 754, 716, 691, 645, 599, 569, 522, 507, 452
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C17H16N3O2
294.1243; Found: 294.1243; mp 183.3-186.6 °C.
3-allyl-6-amino-1-benzylpyrimidine-2,4(1H,3H)-dione
(57), 4.5 mmol scale, solid, 0.51 g, isolated yield 44%; 1H
NMR (700 MHz, DMSO-d6) δ 7.31-7.35 (m, 2H), 7.23-7.27
(m, 1H), 7.17 - 7.20 (m, 2H), 6.84 (s, 2H), 5.78 (ddt, J =
17.2, 10.3, 5.2, 5.2 Hz, 1H), 5.07 (s, 2H), 5.03 (dq, J = 10.3,
1.5 Hz, 2H), 4.99 (dq, J = 17.2, 1.6 Hz, 1H), 4.73 (s, 1H),
4.33 (dt, J = 5.2, 1.5 Hz, 2H); 13C{1H} NMR (176 MHz,
DMSO-d6) δ 160.9, 154.6, 151.4, 136.6, 133.6, 128.5,
127.2, 126.4, 115.7, 75.2, 44.6, 42.0; IR νmax: 3420, 3336,
3182, 1632, 1607, 1579, 1490, 1450, 1418, 1270, 1129,
993, 925, 789, 762, 733, 692, 635, 593, 530, 437 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C14H16N3O2
258.1243; Found: 258.1244; mp 198.1-203.8 °C.
6-amino-1-benzyl-3-(4-methylbenzyl)pyrimidine-
2,4(1H,3H)-dione (61), 2.5 mmol scale, solid, 0.65 g,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
isolated yield 81%; H NMR (700 MHz, DMSO-d6) δ 7.30-
7.34 (m, 2H), 7.22-7.27 (m, 1H), 7.18 (d, J = 7.5 Hz, 2H),
7.05-7.13 (m, 4H), 6.89 (s, 2H), 5.06 (s, 2H), 4.88 (s, 2H),
4.77 (s, 1H), 2.24 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-
d6) δ 161.2, 154.6, 136.5, 136.0, 135.2, 128.8, 128.5,
127.4, 126.4, 79.3, 75.2, 44.7, 42.8, 20.7; IR νmax: 2965,
2933, 2875, 1687, 1612, 1568, 1449, 1416, 1362, 1233,
1116, 814, 767, 570, 551, 471 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C19H20N3O2 322.1556; Found: 322.1555;
mp 83.6-90.2 °C.
6-amino-1-benzyl-3-(4-isopropylbenzyl)pyrimidine-
2,4(1H,3H)-dione (62), 3.6 mmol scale, solid, 0.97 g,
1
isolated yield 76%; H NMR (400 MHz, DMSO-d6) δ 7.13-
7.34 (m, 9H), 6.87 (s, 2H) 5.08 (s, 2H), 4.89 (s, 2H), 4.76 (s,
1H), 2.84-2.82 (m, 1H), 1.17 (d, J = 7.1 Hz, 6H); 13C{1H}
NMR (176 MHz, DMSO-d6) δ 162.0, 159.0, 156.3, 152.1,
147.1, 138.4, 135.4, 128.3, 127.5, 127.2, 126.2, 81.7, 45.3,
43.0, 33.2, 24.0; IR νmax: 3179, 2958, 2869, 1608, 1491,
1451, 1422, 1400, 1351, 1279, 1209, 1188, 1117, 1054,
1018, 930, 783, 726, 694, 595, 529 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C21H24N3O2 350.1869; Found:
350.1868; mp 89.5-93.2 °C.
6-amino-1,3-dibenzylpyrimidine-2,4(1H,3H)-dione (58),
1.2 mmol scale, solid, 0.26 g, isolated yield 72%; 1H NMR
(400 MHz, DMSO-d6) δ 7.12-7.42 (m, 10H), 6.90 (s, 2H),
5.09 (s, 2H), 4.95 (s, 2H), 4.80 (s, 1H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 161.6, 155.1, 152.1, 138.7, 136.9,
128.9, 128.6, 127.7, 127.6, 127.3, 126.8, 75.7, 45.2, 43.5;
IR νmax: 3459, 2966, 1688, 1612, 1568, 1496, 1450, 1414,
1363, 1282, 1118, 813, 755, 738, 694, 593, 534, 507 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C18H18N3O2
308.1399; Found: 308.1399; mp 87.4-90.3 °C. The above
6-amino-1-benzyl-3-(3-methoxybenzyl)pyrimidine-
2,4(1H,3H)-dione (63), 2.0 mmol scale, solid, 0.45 g,
1
isolated yield 65%; H NMR (400 MHz, DMSO-d6) δ 7.17-
7.37 (m, 6H), 6.91 (s, 2H), 6.72-6.82 (m, 3H), 5.09 (s, 2H),
4.92 (s, 2H), 4.80 (s, 1H), 3.70 (s, 3H); 13C{1H} NMR (176
MHz, DMSO-d6) δ 161.2, 159.3, 154.7, 151.7, 139.8,
136.5, 129.3, 128.5, 127.3, 126.4, 119.4, 113.0, 112.2,
75.2, 55.0, 44.7, 43.0; IR νmax: 3446, 3355, 3137, 1702,
1645, 1599, 1490, 1451, 1428, 1403, 1344, 1283, 1259,
1160, 1038, 938, 786, 776, 757, 728, 688, 591, 530, 502
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C19H20N3O3
338.1505; Found: 338.1505; mp 89.4-91.2 °C.
analysis results correspond to the literature data19e
.
6-amino-1-benzyl-3-(2-methylbenzyl)pyrimidine-
2,4(1H,3H)-dione (59), 3.3 mmol scale, solid, 0.65 g,
1
isolated yield 61%; H NMR (700 MHz, DMSO-d6) δ 7.33
(t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.18-7.22 (m,
2H), 7.13 (d, J = 6.9 Hz, 1H), 7.08 (quind, J = 7.0, 7.0, 7.0,
7.0, 1.4 Hz, 2H), 6.96 (s, 2H), 6.78-6.82 (m, 1H), 5.09 (s,
2H), 4.90 (s, 2H), 4.82 (s, 1H), 2.31 (s, 3H); 13C{1H} NMR
(176 MHz, DMSO-d6) δ 161.3, 154.8, 151.8, 136.6, 136.0,
134.9, 129.9, 128.5, 127.2, 126.4, 125.8, 124.6, 75.2, 44.8,
40.9, 18.8; IR νmax: 3425, 3344, 1618, 1582, 1488, 1450,
1417, 1277, 1197, 1028, 948, 790, 746, 728, 703, 648,
593, 549, 503, 430 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C19H20N3O2 322.1556; Found: 322.1557; mp
191.3-197.5 °C.
6-amino-1-benzyl-3-(2-fluorobenzyl)pyrimidine-
2,4(1H,3H)-dione (64), 2.3 mmol scale, solid, 0.49 g,
1
isolated yield 66%; H NMR (700 MHz, DMSO-d6) δ 7.31-
7.35 (m, 2H), 7.23-7.28 (m, 2H), 7.19 (d, J = 7.1 Hz, 2H),
7.12-7.17 (m, 1H), 7.10 (td, J = 7.5, 1.0 Hz, 1H), 6.91-7.03
(m, 3H), 5.08 (s, 2H), 4.99 (s, 2H), 4.80 (s, 1H); 13C{1H} NMR
(176 MHz, DMSO-d6) δ 161.1, 159.2, 154.9, 151.7, 136.5,
128.6 (d, J = 8.2 Hz), 128.6, 127.8 (d, J = 4.5 Hz), 127.2,
126.3, 125.0 (d, J = 14.3 Hz), 124.4 (d, J = 3.7 Hz), 115.2 (d,
J = 21.3 Hz), 75.1, 44.8, 37.0 (d, J = 5.3 Hz); IR νmax: 3464,
3319, 3190, 1692, 1608, 1580, 1487, 1453, 1418, 1360,
1274, 1221, 1193, 834, 778, 758, 734, 693, 523 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C18H17FN3O2
326.1305; Found: 326.1307; mp 176.9-181.6 °C.
6-amino-1-benzyl-3-(3-methylbenzyl)pyrimidine-
2,4(1H,3H)-dione (60), 2.0 mmol scale, solid, 0.50 g,
1
isolated yield 79%; H NMR (700 MHz, DMSO-d6) δ 7.31-
7.35 (m, 2H), 7.23-7.27 (m, 1H), 7.17-7.20 (m, 2H), 7.13-
7.17 (m, 1H), 6.98-7.04 (m, 3H), 6.90 (s, 2H), 5.07 (s, 2H),
4.89 (s, 2H), 4.77 (s, 1H), 2.24 (s, 3H); 13C{1H} NMR (176
6-amino-1-benzyl-3-(3-fluorobenzyl)pyrimidine-
2,4(1H,3H)-dione (65), 2.6 mmol scale, solid 0.64 g,
1
isolated yield 75%; H NMR (700 MHz, DMSO-d6) δ 7.30-
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7.35 (m, 3H), 7.24-7.27 (m, 1H), 7.18 (d, J = 7.3 Hz, 2H),
5-(4-methoxyphenyl)-1,3-dipropyl-5,8-dihydro-
2
7.03-7.06 (m, 2H), 6.98-7.01 (m, 1H), 6.95 (s, 2 H), 5.07 (s,
2H), 4.93 (s, 2H), 4.79 (s, 1H); 13C{1H} NMR (176 MHz,
DMSO-d6) δ 161.5, 161.1, 154.8, 151.7, 141.2 (d, J = 7.4
Hz), 136.5, 130.3 (d, J = 8.2 Hz), 128.5, 127.3, 126.4, 123.3
(d, J = 2.5 Hz), 114.0 (d, J = 21.7 Hz), 113.7 (d, J = 20.9 Hz),
75.1, 44.8, 42.7; IR νmax: 3461, 3371, 3135, 1697, 1609,
1498, 1428, 1409, 1269, 1253, 1116, 932, 793, 775, 761,
713, 684, 660, 596, 534 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C18H17FN3O2 326.1305; Found: 326.1305; mp
90.3-95.1 °C.
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aaa),
solid, 106 mg, isolated yield 95%.; H NMR (700 MHz,
3
4
5
6
7
8
9
1
CDCl3) δ 8.61 (s, 1H), 7.14-7.18 (m, 2H), 6.79-6.83 (m, 2H),
4.43 (d, J = 6.56 Hz, 1H), 3.85-3.97 (m, 4H), 3.76 (s, 3H),
2.94-3.00 (m, 1H), 2.87 (dd, J = 1.40, 16.46 Hz, 1H), 1.61-
1.73 (m, 5H), 0.96 (t, J = 7.37 Hz, 3H), 0.92 (t, J = 7.48 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 161.2, 158.8,
150.8, 143.8, 133.5, 127.5, 114.3, 93.1, 55.2, 44.2, 43.4,
37.8, 33.0, 22.1, 21.0, 11.3, 10.7; IR νmax: 3156.1, 2965.2,
2923.6, 1686.7, 1645.9, 1632.8, 1608.0, 1509.5, 1491.6,
1454.8, 1440.2, 1417.7, 1375.4, 1353.9, 1302.6, 1257.8,
1235.4, 1203.8, 1175.4, 1153.3, 1031.4, 998.3, 831.8,
776.1, 760.1, 739.0, 717.2, 687.0, 649.5, 584.3, 554.9,
530.0, 518.6, 496.6, 462.0 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C20H26N3O4 372.1923; Found: 372.1924;
mp 174.2-176.7 °C.
5-phenyl-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7baa), solid,
113 mg, isolated yield 83%; 1H NMR (700 MHz, CDCl3)
δ 9.37 (s, 1H), 7.25-7.30 (m, 2H), 7.20-7.24 (m, 3H), 4.48
(d, J = 6.99 Hz, 1H), 3.98 (ddd, J = 6.10, 10.00, 14.90 Hz,
1H), 3.83-3.93 (m, 3H), 3.00 (dd, J = 8.01, 16.51 Hz, 1H),
2.87 (dd, J = 1.02, 16.51 Hz, 1H), 1.57-1.69 (m, 4H), 0.91
(dt, J = 2.04, 7.42 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3)
δ 172.4, 161.2, 150.8, 144.0, 141.4, 128.9, 127.3, 126.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-amino-1-benzyl-3-(3-bromobenzyl)pyrimidine-
2,4(1H,3H)-dione (66), 3.5 mmol scale, solid, 0.93 g,
1
isolated yield 69%; H NMR (400 MHz, DMSO-d6) δ 7.43
(dt, J = 6.3, 2.1 Hz, 1H), 7.39 (s, 1H), 7.31-7.37 (m, 2H),
7.23-7.30 (m, 3H), 7.20 (d, J = 7.3 Hz, 2H), 6.96 (s, 2H),
5.10 (s, 2H), 4.94 (s, 2H), 4.81 (s, 1H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 161.5, 155.2, 152.1, 141.5, 136.9,
130.9, 130.4, 130.2, 128.9, 127.7, 126.9, 126.7, 122.0,
75.6, 45.2, 43.0; IR νmax: 3435, 3133, 1702, 1640, 1604,
1493, 1427, 1402, 1281, 1215, 1070, 935, 880, 784, 768,
725, 692, 666, 588, 534, 507, 462, 423 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C18H17BrN3O2 386.0504;
Found: 386.0502; mp 86.6-88.5 °C.
6-amino-1-benzyl-3-(3-trifluoromethyl)benzyl)-
pyrimidine-2,4(1H,3H)-dione (67), 2.7 mmol scale, solid,
0.68 g, isolated yield 67%; 1H NMR (400MHz, DMSO-d6) δ
7.50-7.64 (m, 4H), 7.23-7.37 (m, 3H), 7.13-7.22 (m, 2H),
6.91-7.04 (m, 2H), 5.09 (s, 2H), 5.02 (s, 2H), 4.80 (s, 1H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 161.5, 155.2, 152.2,
140.1, 136.8, 132.0, 129.8, 129.5 (q, J = 31.8 Hz), 128.9,
127.7, 126.7, 123.8-124.4 (m), 124.7 (q, J = 271.8 Hz),
75.6, 45.2, 43.2; IR νmax: 3434, 3138, 1643, 1605, 1497,
1450, 1406, 1326, 1281, 1157, 1122, 1073, 938, 790, 728,
695, 659, 535, 509 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C19H17F3N3O2 376.1273; Found: 376.1274; mp
95.8-102.3 °C.
92.7, 44.2, 43.4, 37.7, 33.8, 22.1, 21.0, 11.3, 10.7; IR νmax
:
3246.8, 3217.6, 2963.0, 2933.5, 1687.6, 1654.9, 1632.6,
1504.3, 1480.4, 1471.1, 1441.4, 1417.7, 1353.8, 1300.8,
1281.2, 1242.6, 1227.0, 1173.6, 1137.5, 759.8, 741.3,
695.9, 683.2, 646.5, 565.7, 552.8, 496.2, 441.7 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C19H24N3O3
342.1818; Found: 342.1819; mp 173.6-175.0 °C.
5-(2-methoxyphenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-
d]pyrimidine-2,4,7(1H,3H,6H)-trione (7caa), solid, 149
1
mg, isolated yield 79%; H NMR (700 MHz, CDCl3) δ 8.10
(s, 1H), 7.18-7.23 (m, 1H), 7.05 (dd, J = 1.72, 7.53 Hz, 1H),
6.83-6.87 (m, 2H), 4.63 (d, J = 7.96 Hz, 1H), 3.81-3.97 (m,
4H), 3.79 (s, 3H), 2.93 (dd, J = 9.09, 16.83 Hz, 1H), 2.80
(dd, J = 1.02, 16.73 Hz, 1H), 1.61 (dt, J = 1.40, 7.53 Hz, 4H),
0.98 (t, J = 7.42 Hz, 3H), 0.89 (t, J = 7.42 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 172.5, 161.0, 157.0, 150.9,
144.6, 128.8, 128.5, 128.0, 120.5, 110.8, 90.9, 54.8, 44.1,
43.2, 36.6, 30.8, 22.1, 21.0, 11.3, 10.7; IR νmax: 3203.0,
2963.4, 2934.6, 1719.4, 1691.7, 1635.0, 1612.6, 1510.8,
1487.6, 1475.9, 1455.0, 1424.9, 1359.0, 1334.2, 1284.8,
1235.7, 1177.0, 1109.6, 1028.1, 754.1, 657.3, 488.8 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C20H26N3O4
372.1923; Found: 372.1922; mp 219.0-220.3 °C.
6-amino-1-benzyl-3-(4-nitrobenzyl)pyrimidine-
2,4(1H,3H)-dione (68), 3.1 mmol scale, solid, 0.64 g,
1
isolated yield 58%; H NMR (700 MHz, DMSO-d6) δ 8.16
(d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 7.5
Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H),
7.00 (s, 2H), 5.06 (d, J = 18.9 Hz, 4H), 4.81 (s, 1H); 13C{1H}
NMR (176 MHz, DMSO-d6) δ 161.0, 154.9, 151.7, 146.6,
146.2, 136.4, 128.6, 128.2, 127.3, 126.3, 123.6, 75.1, 44.8,
42.9; IR νmax: 3428, 1689, 1643, 1602, 1518, 1493, 1451,
1405, 1343, 1285, 1215, 1208, 1110, 855, 804, 745, 693,
639, 598, 548, 522, 453 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C18H17N4O4 353.1250; Found: 353.1247; mp
153.0-158.5 °C.
General procedure for the catalytic reactions.
Corresponding 1,3-disubstituted 6-aminouracil (0.3
mmol), NHC precatalyst 8c (0.03 mmol; 8 mg),
Kharach oxididant DQ (0.3 mmol; 122 mg) and α,β-
unsaturated aldehyde (0.3 mmol) were dispersed in
anhydrous toluene (3 mL). Anhydrous potassium
phosphate tribasic (0.06 mmol; 13 mg) as a base was
added and mixture was stirred at room temperature
for 24 hours. The final product was isolated by flash
column chromatography using gradient elution (0-
100% AcOEt in hexanes).
3-methoxy-4-(2,4,7-trioxo-1,3-dipropyl-1,2,3,4,5,6,7,8-
octahydropyrido[2,3-d]pyrimidin-5-yl)phenyl
acetate
1
(7daa), solid, 124 mg, isolated yield 72%; H NMR (700
MHz, CDCl3) δ 7.04 (d, J = 2.04 Hz, 1H), 6.91 (d, J = 8.17 Hz,
1H), 6.76 (d, J = 8.28 Hz, 1H), 4.50 (dd, J = 3.44, 6.02 Hz,
1H), 3.84-3.95 (m, 4H), 3.78 (s, 3H), 2.96 (d,
J = 6.24 Hz, 2H), 2.29 (s, 3H), 1.60-1.75 (m, 4H), 0.99 (t, J
= 7.42 Hz, 3H), 0.93 (t, J = 7.48 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 172.4, 169.1, 161.3, 151.3, 150.7, 143.9,
140.3, 138.9, 122.8, 117.6, 111.7, 92.8, 55.8, 44.3, 43.4,
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37.0, 33.4, 22.1, 21.0, 20.6, 11.3, 10.7; IR νmax: 2957.9,
1.60 (m, 4H), 0.97-0.88 (m, 6H); 13C{1H} NMR (101 MHz,
2926.2, 1767.7, 1689.5, 1637.6, 1603.8, 1504.8, 1477.7,
1458.7, 1419.6, 1365.1, 1355.3, 1332.1, 1293.3, 1269.2,
1258.3, 1233.5, 1191.0, 1176.8, 1160.9, 1135.2, 1120.3,
1033.0, 1012.0, 892.4, 757.3, 743.8, 678.4, 502.3, 473.7,
457.7 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C22H28N3O6 430.1978; Found: 430.1980; mp 176.3-177.4
°C.
1,3-dipropyl-5-(p-tolyl)-5,8-dihydropyrido[2,3-d]pyrimi-
dine-2,4,7(1H,3H,6H)-trione (7eaa), solid, 85 mg, isolated
yield 61%; 1H NMR (700 MHz, CDCl3) δ 8.07 (s, 1H), 7.11-
7.16 (m, 2H), 7.07-7.10 (m, 2H), 4.45 (d, J = 6.67 Hz, 1H),
3.83-3.94 (m, 4H), 2.98 (dd, J = 7.80, 16.60 Hz, 1H), 2.89
(dd, J = 1.10, 16.50 Hz, 1H), 2.29 (s, 3H), 1.60-1.75 (m, 4H),
0.98 (t, J = 7.42 Hz, 3H), 0.92 (t, J = 7.48 Hz, 3H);
13C{1H} NMR (176 MHz, CDCl3) δ 170.7, 160.6, 150.3,
143.1, 138.0, 136.6, 129.2, 125.9, 92.6, 43.8, 43.0, 37.0,
33.1, 21.8, 20.6, 20.6, 10.9, 10.5; IR νmax: 3167.0, 2967.6,
2933.9, 1686.8, 1648.7, 1633.7, 1493.5, 1457.1, 1353.7,
1238.8, 774.0, 495.5 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C20H26N3O3 356.1974; Found: 356.1974; mp
169.3-171.5 °C.
CDCl3) δ 171.8, 161.0, 150.7, 144.0, 140.4, 132.0, 128.2,
121.3, 92.2, 44.3, 43.4, 37.4, 33.4, 22.1, 21.0, 11.3, 10.8;
IR νmax: 2965.6, 2930.8, 1688.2, 1643.4, 1632.5, 1490.7,
1463.8, 1453.9, 1441.8, 1422.8, 1351.3, 1316.0, 1298.8,
1240.2, 1142.3, 1075.5, 1011.2, 1000.4, 836.5, 782.4,
3
4
5
6
7
8
9
755.3,
743.0,
555.0,
495.0
cm-1;
HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C19H23BrN3O3 420.0923;
Found: 420.0923; mp 72.0-76.0 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(4-nitrophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7iaa), solid, 75 mg,
1
isolated yield 65%; H NMR (400 MHz, CDCl3) δ 8.49 (s,
1H), 8.14-8.21 (m, 2H), 7.41-7.48 (m, 2H), 4.61 (d,
J = 6.8 Hz, 1H), 3.87-4.03 (m, 4H), 3.10 (dd, J = 16.9, 8.1
Hz, 1H), 2.92 (dd, J = 16.9, 1.5 Hz, 1H), 1.61-1.70 (m, 4H),
1.00 (t, J = 7.3 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 170.5, 160.9, 150.5, 148.8, 147.3,
144.1, 127.5, 124.2, 91.4, 44.4, 43.5, 36.9, 33.9, 22.2,
21.0, 11.3, 10.9; IR νmax: 3244.7, 3192.1, 2967.7, 2937.4,
2876.6, 1685.1, 1633.1, 1513.8, 1470.1, 1346.7, 1308.4,
1269.3, 1238.0, 1174.7, 1152.2, 1111.0, 856.0, 787.5,
749.8, 704.4, 685.5, 61.6, 485.8 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C19H23N4O5 387.1668; Found:
387.1669; mp 194.4-197.9 °C.
5-(4-fluorophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7faa), solid, 110 mg,
1
isolated yield 77%; H NMR (700 MHz, CDCl3) δ 8.41 (s,
3-benzyl-5-(furan-2-yl)-1-propyl-5,8-dihydropyrido[2,3-
d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7jba), solid, 76 mg
1H), 7.18-7.22 (m, 2H), 6.95-6.99 (m, 2H), 4.47 (d, J = 6.99
Hz, 1H), 3.85-3.97 (m, 4H), 3.00 (dd, J = 8.01, 16.51 Hz,
1H), 2.86 (dd, J = 1.40, 16.56 Hz, 1H), 1.61-1.75 (m, 4H),
0.97 (t, J = 7.42 Hz, 3H), 0.92 (t, J = 7.42 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ172.0, 163.2, 161.1,
160.8, 150.7, 143.9, 137.1 (d, J = 3.18 Hz), 128.0 (d, J =
7.95 Hz), 115.8 (d, J = 21.50 Hz), 92.6, 44.3, 43.4, 37.7,
33.2, 22.1, 21.0, 11.3, 10.7; IR νmax: 3242.4, 3187.6,
2967.5, 2929.6, 1687.3, 1636.8, 1605.1, 1506.1, 1464.8,
1438.4, 1409.7, 1380.9, 1353.2, 1299.3, 1268.4, 1229.0,
1158.3, 1021.1, 833.3, 781.8, 754.2, 738.5, 684.3, 664.2,
575.4, 551.2, 496.2, 460.8 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C19H23FN3O3 360.1723; Found: 360.1722;
mp 166.3-168.7 °C.
5-(4-chlorophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7gaa), solid, 148 mg,
isolated yield 98%; 1H NMR (700 MHz, CDCl3) δ 7.22-7.28
(m, 2H), 7.13-7.18 (m, 2H), 4.45 (d, J = 6.78 Hz, 1H), 4.00
(ddd, J = 6.10, 10.00, 15.10 Hz, 1H), 3.85-3.93 (m, 3H),
3.00 (dd, J = 8.07, 16.56 Hz, 1H), 2.83 (dd, J = 0.86, 16.56
Hz, 1H), 1.58-1.69 (m, 4H), 0.90-0.93 (m, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 172.1, 161.1, 150.7, 144.1, 139.8,
133.2, 129.1, 127.9, 92.3, 44.3, 43.4, 37.5, 33.3, 22.1,
21.0, 11.3, 10.7; IR νmax: 3245.9, 2958.4, 2925.1, 1688.4,
1632.8, 1506.6, 1492.8, 1470.9, 1435.8, 1422.8, 1347.7,
1299.1, 1233.4, 835.1, 784.5, 750.2, 723.0, 681.4, 669.6,
504.5, 491.7, 460.0 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C19H23ClN3O3 376.1428; Found: 376.1430; mp
128.0-134.0 °C.
1
isolated yield 67%; H NMR (700 MHz, CDCl3) δ 9.00 (s,
1H), 7.47 (d, J = 6.9 Hz, 1H), 7.21-7.33 (m, 4H), 6.25 (dd, J
= 3.2, 1.9 Hz, 1H), 6.09 (dt, J = 3.2, 0.8 Hz, 1H), 5.12 (dd, J
= 18.1, 13.8 Hz, 2H), 4.53 (d, J = 6.7 Hz, 1H), 3.91 (dddd, J
= 38.7, 15.1, 10.1, 6.0 Hz, 2H), 2.94 (dd, J = 16.4, 1.3 Hz,
1H), 2.86 (dd, J = 16.4, 7.5 Hz, 1H), 1.61-1.69 (m, 2H), 0.95
(t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.4,
160.7, 153.7, 150.8, 144.4, 142.1, 136.9, 129.1, 128.4,
127.6, 110.3, 105.7, 90.5, 44.9, 44.4, 35.2, 28.6, 22.1,
10.7; IR νmax: 3164.7, 2964.7, 2933.0, 2876.4, 1688.1,
1635.7, 1500.2, 1477.0, 1350.2, 1322.5, 1290.8, 1239.0,
1147.8, 1133.3, 1012.6, 776.6, 753.5, 734.0, 714.0, 692.7,
657.4, 598.7, 542.7, 480.6 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C21H22N3O4 380.1610; Found: 380.1608;
mp 166.8-168.9 °C.
3-benzyl-5-methyl-1-propyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7kba), solid, 65 mg,
1
isolated yield 66%; H NMR (400 MHz, CDCl3) δ 8.62 (s,
1H), 7.47-7.53 (m, 2H), 7.28-7.37 (m, 3H), 5.15 (s, 2H),
3.85-3.97 (m, 2H), 3.35 (quind, J = 7.1, 1.6 Hz, 1H), 2.73
(dd, J = 16.4, 7.3 Hz, 1H), 2.50 (dd, J = 16.4, 1.2 Hz, 1H),
1.59-1.79 (m, 2 H), 1.14 (d, J = 7.1 Hz, 3H), 1.00 (t, J = 7.5
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 160.9,
150.9, 143.0, 137.0, 129.1, 128.4, 127.6, 94.5, 44.8, 44.3,
37.7, 24.2, 22.1, 18.8, 10.9; IR νmax: 3237.4, 3182.1,
2964.9, 2935.5, 2876.2, 1690.0, 1627.3, 1502.8, 1475.1,
1433.8, 1357.6, 1328.2, 1298.5, 1242.0, 1183.4, 1069.8,
1027.8, 770.7, 751.7, 698.5, 595.1, 495.7, 459.3 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C18H22N3O3
328.1661; Found: 328.1663; 79.8-82.5 °C.
5-(4-bromophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-
d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7haa), solid, 167
1
mg, isolated yield 99%; H NMR (700 MHz, CDCl3) δ 9.15
3-benzyl-5-ethyl-1-propyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7lba), solid, 68 mg,
(s, 1H), 7.43-7.37 (m, 2H), 7.13-7.08 (m, 2H), 4.44 (d, J =
6.8 Hz, 1H), 4.02-3.95 (m, 1H), 3.93-3.86 (m, 3H), 3.00 (dd,
J = 8.1, 16.6 Hz, 1H), 2.83 (dd, J = 0.9, 16.6 Hz, 1H), 1.70-
1
isolated yield 66%; H NMR (400 MHz, CDCl3) δ 7.88 (s,
1H), 7.47-7.52 (m, 2H), 7.28-7.35 (m, 3H), 5.15 (dd, J =
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17.1, 13.4 Hz, 2H), 3.87 (t, J = 7.8 Hz, 2H), 3.17 (m, J = 8.7,
J = 21.3, 13.9 Hz, 2H), 3.97 (dddd, J = 38.4, 14.9, 9.5, 7.1
2
8.7, 5.4 Hz, 1H), 2.64-2.68 (m, 2H), 1.60-1.80 (m, 3H), 1.43
(m, J = 8.3 Hz, 1H), 0.92-1.04 (m, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 172.2, 161.1, 150.9, 143.3, 137.1, 129.1,
128.4, 127.6, 93.6, 44.8, 44.3, 34.9, 30.4, 26.0, 22.1, 11.0,
10.8; IR νmax: 3190.1, 2962.0, 2931.9, 2874.7, 1689.2,
1624.8, 1502.7, 1472.1, 1434.2, 1362.0, 1297.2, 1235.6,
1182.9, 1073.1, 768.4, 750.9, 698.1, 493.9 cm-1; HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C19H24N3O3 342.1818;
Found: 342.1819; mp 82.0-90.8 °C.
Hz, 2H), 3.15-3.28 (m, 1H), 2.55-2.71 (m, 2H), 1.59-1.77
(m, 2H), 1.45-1.57 (m, 1H), 1.17-1.45 (m, 11H), 0.99 (t, J =
7.3 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) ) δ 173.4, 161.2, 150.9, 143.5, 137.1, 129.0, 128.4,
127.6, 94.0, 44.8, 44.3, 35.3, 33.0, 31.8, 29.5, 29.2, 28.8,
26.6, 22.6, 22.1, 14.1, 10.7; IR νmax: 3234.8, 3176.0,
2953.6, 2922.4, 2851.1, 1681.9, 1639.1, 1495.1, 1475.2,
1429.8, 1360.7, 1317.2, 1289.9, 1242.4, 1185.3, 1137.5,
1090.6, 1050.2, 951.5, 751.2, 693.0, 663.9, 653.6, 593.5,
485.9, 439.9 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C24H34N3O3 412.2600; Found: 412.2601.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-benzyl-1,5-dipropyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7mba), solid, 74 mg,
1
isolated yield 70%; H NMR (400 MHz, CDCl3) δ 8.69 (s,
3-benzyl-5-nonyl-1-propyl-5,8-dihydropyrido[2,3-d]-
1H), 7.45-7.54 (m, 2H), 7.28-7.36 (m, 3H), 5.11-5.20 (m,
2H), 3.84-4.00 (m, 2H), 3.19-3.29 (m, 1H), 2.58-2.70 (m,
2H), 1.64-1.77 (m, 2H), 1.26-1.55 (m, 4H), 1.00 (t, J = 7.5
Hz, 3H), 0.93 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 172.3, 161.1, 150.9, 143.3, 137.1, 129.0, 128.4,
127.6, 94.0, 44.8, 44.3, 35.3, 35.2, 28.7, 22.1, 19.8, 13.9,
10.8; IR νmax: 3244.9, 3193.4, 2963.8, 2934.6, 2876.4,
1690.8, 1627.5, 1512.2, 1475.7, 1433.0, 1357.0, 1300.8,
1246.3, 1184.0, 1069.9, 755.7, 699.8, 596.9, 548.4, 497.8,
460.5 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C20H26N3O3 356.1974; Found: 356.1974; 133.5-141.8 °C.
3-benzyl-5-pentyl-1-propyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7nba), solid, 52 mg,
pyrimidine-2,4,7(1H,3H,6H)-trione (7qba) viscous oil,
1
61 mg, isolated yield 46%; H NMR (700 MHz, CDCl3) δ
9.53 (s, 1H), 7.43-7.50 (m, 2H), 7.21-7.32 (m, 3H), 5.14
(dd, J = 30.3, 13.8 Hz, 2H), 3.99 (ddd, J = 14.6, 10.3, 6.2 Hz,
1H), 3.90 (ddd, J = 15.0, 9.9, 5.5 Hz, 1H), 3.15-3.23 (m, 1H),
2.56-2.66 (m, 2H), 1.58-1.71 (m, 2H), 1.44-1.52 (m, 1H),
1.21-1.38 (m, 15H), 0.97 (t, J = 7.3 Hz, 3H), 0.87 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 173.0, 160.8,
150.5, 143.1, 136.7, 128.6, 128.0, 127.2, 93.6, 44.4, 43.9,
34.9, 32.6, 31.5, 29.2, 29.2, 29.1, 28.9, 28.4, 26.2, 22.3,
21.7, 13.7, 10.3; IR νmax: 3234.2, 3182.2, 2924.0, 2853.0,
1690.7, 1631.9, 1503.9, 1472.5, 1435.3, 1361.0, 1299.2,
1242.4, 1183.4, 751.6, 697.8, 594.5, 493.8 cm-1; HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C26H37N3O3 440.2835;
Found: 440.2835.
1
isolated yield 45%; H NMR (400 MHz, CDCl3) δ 9.41 (s,
1H), 7.42-7.55 (m, 2H), 7.20-7.37 (m, 3H), 5.16 (dd, J =
21.0, 13.7 Hz, 2H), 3.96 (dddd, J = 36.0, 14.9, 9.3, 6.6 Hz,
2H), 3.15-3.28 (m, 1H), 2.56-2.70 (m, 2H), 1.60-1.76 (m,
2H), 1.46-1.56 (m, 1H), 1.20-1.44 (m, 7H), 0.99 (t, J = 7.3
Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 173.1, 161.2, 150.9, 143.5, 137.1, 129.0, 128.4,
127.5, 94.0, 44.8, 44.3, 35.3, 33.0, 31.7, 28.8, 26.2, 22.5,
22.1, 14.0, 10.7; IR νmax: 3235.1, 3186.1, 2960.6, 2928.1,
2854.0, 1687.6, 1634.0, 1503.3, 1468.8, 1432.3, 1360.8,
1295.2, 1242.2, 1177.0, 1072.7, 750.7, 701.5, 595.0,
493.6 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C22H30N3O3 384.2287; Found: 384.2288; mp 107.5-108.9
°C.
3-benzyl-5-decyl-1-propyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7rba), viscous oil, 83
1
mg, isolated yield 61%; H NMR (700 MHz, CDCl3) δ 9.19
(s, 1H), 7.45-7.49 (m, 2H), 7.28-7.32 (m, 2H), 7.23-7.25 (m,
1H), 5.13 (dd, J = 27.6, 13.8 Hz, 2H), 3.92-3.99 (m, 1H),
3.88 (ddd, J = 14.6, 9.9, 5.4 Hz, 1H), 3.16-3.22 (m, 1H),
2.57-2.66 (m, 2H), 1.58-1.72 (m, 2H), 1.43-1.52 (m, 1H),
1.23-1.38 (m, 17H), 0.97 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 173.2, 160.8,
150.5, 143.1, 136.7, 128.6, 128.0, 127.2, 93.7, 44.4, 44.0,
34.9, 32.6, 31.5, 29.2, 29.2, 29.2, 28.9, 28.4, 26.2, 22.3,
21.7, 13.7, 10.3; IR νmax: 3234.3, 3191.5, 2923.2, 2852.7,
1691.7, 1632.6, 1504.1, 1472.8, 1435.5, 1361.6, 1299.7,
1241.7, 1183.8, 1074.1, 752.1, 698.0, 594.8, 493.5 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C27H40N3O3
454.3070; Found: 454.3069.
(E)-3-benzyl-5-(prop-1-en-1-yl)-1-propyl-5,8-dihydro-
-pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7sba),
solid, 71 mg, isolated yield 67%; 1H NMR (400 MHz, CDCl3
δ 9.20 (s, 1H), 7.44-7.56 (m, 2H), 7.20-7.39 (m, 3H), 5.47-
5.61 (m, 1H), 5.42 (ddd, J = 15.4, 5.9, 1.5 Hz, 1H), 5.15 (s,
2H), 3.95 (dddd, J = 27.1, 14.9, 9.5, 5.9 Hz, 2H), 3.83 (td, J
= 5.7, 1.3 Hz, 1H), 2.62-2.78 (m, 2H), 1.58-1.80 (m, 5H),
1.00 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101MHz, CDCl3) δ
172.4, 160.9, 150.9, 143.6, 137.0, 129.1, 128.6, 128.4,
127.6, 125.9, 92.3, 44.8, 44.4, 36.0, 31.1, 22.1, 17.8, 10.8;
IR-ATR νmax: 3192.3, 2965.1, 2935.2, 2876.9, 1688.9,
1625.8, 1502.4, 1472.3, 1435.0, 1354.0, 1289.4, 1231.4,
1179.6, 1073.6, 964.6, 751.4, 697.6, 490.9, 466.0 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C20H24N3O3
354.1818; Found: 354.1818; mp 58.9-61.5 °C.
3-benzyl-5-hexyl-1-propyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7oba), viscous oil, 72
1
mg, isolated yield 60%; H NMR (400 MHz, CDCl3) δ 9.39
(s, 1H), 7.45-7.52 (m, 2H), 7.22-7.36 (m, 3H), 5.16 (dd, J =
21.0, 13.7 Hz, 2H), 3.96 (dddd, J = 36.2, 15.2, 9.5, 6.6 Hz,
2H), 3.16-3.27 (m, 1H), 2.56-2.71 (m, 2H), 1.58-1.78 (m,
2H), 1.45-1.58 (m, 1H), 1.16-1.45 (m, 9H), 0.99 (t, J = 7.3
Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 173.1, 161.2, 150.9, 143.4, 137.1, 129.0, 128.4,
127.5, 94.0, 44.8, 44.3, 35.4, 33.0, 31.7, 29.2, 28.8, 26.5,
22.5, 22.1, 14.0, 10.7; IR νmax: 3223.8, 3174.9, 2949.7,
2926.6, 2855.4, 1682.8, 1635.1, 1496.6, 1475.1, 1431.1,
1358.8, 1325.1, 1295.9, 1240.1, 1184.4, 769.6, 751.8,
723.1, 694.3, 664.4, 594.2, 489.1 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C23H32N3O3 398.2444; Found:
398.2442.
3-benzyl-5-heptyl-1-propyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,6H)-trione (7pba), viscous oil, 67
1
mg, isolated yield 55%; H NMR (400 MHz, CDCl3) δ 9.61
(s, 1H), 7.49 (d, J = 6.8 Hz, 2H), 7.22-7.36 (m, 3H), 5.16 (dd,
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1-benzyl-5-(4-methoxyphenyl)-3-propyl-5,8-dihydro-
834.3, 779.2, 755.0, 659.5, 529.0, 495.1, 474.1 cm-1;
-pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aab),
solid, 97 mg, isolated yield 77%; 1H NMR (700 MHz, CDCl3)
δ 7.96 (s, 1H), 7.32-7.39 (m, 3H), 7.20-7.23 (m, 2H), 7.07-
7.11 (m, 2H), 6.76-6.79 (m, 2H), 5.42 (d, J = 16.78 Hz, 1H),
5.07 (d, J = 16.78 Hz, 1H), 4.40 (dd, J = 1.18, 7.85 Hz, 1H),
3.94 (dddd, J = 6.30, 8.60, 12.80, 21.70 Hz, 2H), 3.75 (s,
3H), 2.89 (dd, J = 8.00, 16.40 Hz, 1H), 2.78 (dd, J = 1.08,
16.35 Hz, 1H), 1.68 (dddt, J = 1.24, 5.08, 6.28, 7.47 Hz, 2H),
0.94 (t, J = 7.42 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
170.5, 161.0, 158.8, 151.2, 144.0, 134.5, 133.3, 129.6,
128.7, 127.5, 126.2, 114.3, 93.7, 55.3, 46.0, 43.6, 37.7,
33.4, 21.0, 11.3; IR νmax: 3234, 3186, 2957, 1688, 1643,
1633, 1510, 1457, 1439, 1350, 1299, 1248, 1186, 1154,
1119, 1035, 848, 781, 756, 732, 692, 672, 576, 525, 505,
477, 456 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C24H26N3O4 420.1923; Found: 420.1925; mp 167.4-176.8
°C.
5-(4-methoxyphenyl)-1-phenyl-3-propyl-5,8-dihydro-
-pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aac),
solid, 68 mg, isolated yield 56%; 1H NMR (700 MHz, CDCl3)
δ 7.57-7.62 (m, 3H), 7.30-7.35 (m, 2H), 7.21-7.24 (m, 2H),
6.82-6.86 (m, 2H), 6.74 (s, 1H), 4.48 (dd, J = 8.0, 1.5 Hz,
1H), 3.86-3.95 (m, 2H), 3.78 (s, 3H), 3.00 (dd, J = 16.7, 8.1
Hz, 1H), 2.87 (dt, J = 16.4, 1.4 Hz, 1H), 1.67 (ddt, J = 7.6,
6.3, 1.2, 1.2 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C{1H} NMR
(176 MHz, CDCl3) δ 169.1, 160.8, 158.4, 150.1, 142.4,
133.4, 131.9, 130.5, 130.5, 130.4, 128.9, 128.6, 127.2,
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C21H28N3O4
386.2080; Found: 386.2082; mp 146.3-147.7 °C.
3-isobutyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aea),
solid, 87 mg; isolated yield 75%; 1H NMR (400 MHz, CDCl3)
δ 8.97 (s, 1H), 7.14-7.19 (m, 2H), 6.80-6.85 (m, 2H), 4.46
(d, J = 6.4 Hz, 1H), 3.88-4.04 (m, 2 H), 3.80 (t, J = 7.1 Hz, 2
H), 3.77 (s, 3H), 3.00 (dd, J = 16.6, 7.8 Hz, 1H), 2.88 (dd, J
= 16.4, 1.5 Hz, 1H), 2.13 (spt, J = 7.0 Hz, 1H), 1.61-1.73 (m,
2H), 0.88-0.99 (m, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
172.1, 161.4, 158.8, 151.0, 143.6, 133.4, 127.5, 114.3,
93.0, 55.2, 48.6, 44.2, 37.7, 33.1, 27.1, 22.1, 20.2, 20.1,
10.8; IR νmax: 3165.2, 2959.4, 2874.0, 2833.6, 1683.2,
1636.2, 1509.4, 1477.4, 1332.3, 1295.6, 1250.2, 1233.1,
1175.2, 1147.3, 1086.9, 1034.0, 834.2, 779.2, 754.2,
658.3, 474.2 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C21H28N3O4 386.2080; Found: 386.2081; mp 153.8-156.9
°C.
1,3-dibutyl-5-(4-methoxyphenyl)-5,8-dihydropyrido-
[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7afd), solid, 92
mg, isolated yield 77%; 1H NMR (700 MHz, CDCl3) δ 8.10-
8.16 (m, 1H), 7.17-7.21 (m, 2H), 6.83-6.87 (m, 2H), 4.47
(d, J = 6.5 Hz, 1H), 3.90-4.00 (m, 4H), 3.79 (s, 3H), 3.00 (dd,
J = 16.6, 7.7 Hz, 1H), 2.91 (dd, J = 16.7, 1.4 Hz, 1H), 1.61-
1.63 (m, 4H), 1.35-1.47 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H),
0.96 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ
172.0, 162.0, 159.8, 151.7, 144.4, 134.5, 128.5, 115.3,
94.2, 56.3, 43.7, 42.7, 38.6, 34.2, 31.9, 30.8, 21.2, 20.9,
14.7, 14.6; IR νmax: 3223.5, 3176.3, 2958.4, 2931.7,
2872.3, 1684.9, 1634.4, 1505.3, 1472.4, 1356.9, 1297.7,
1247.4, 1224.6, 1175.6, 1148.0, 1030.4, 831.5, 780.8,
755.3, 685.4, 658.2, 556.6, 529.2 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C22H30N3O4 400.2236; Found:
400.2236; mp 95.7-98.9 °C.
5-(4-methoxyphenyl)-3-pentyl-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aga),
solid, 82 mg, isolated yield 69%; 1H NMR (700 MHz, CDCl3)
δ 8.52 (s, 1H), 7.13-7.18 (m, 2H), 6.79-6.84 (m, 2H), 4.44
(dd, J = 7.9, 1.4 Hz, 1H), 3.85-3.96 (m, 4H), 3.76 (s, 3H),
2.94-3.00 (m, 1H), 2.87 (dd, J = 16.3, 0.9 Hz, 1H), 1.56-1.66
(m, 4H), 1.27-1.35 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.5,
161.0, 158.8, 150.7, 143.5, 133.5, 127.5, 114.3, 93.2, 55.3,
44.2, 41.9, 37.6, 33.1, 29.1, 27.3, 22.4, 22.2, 14.0, 10.9; IR
νmax: 2958.8, 2932.9, 1687.4, 1634.4, 1506.1, 1474.2,
1355.6, 1296.4, 1234.6, 1176.7, 1032.2, 831.5, 780.9,
755.6 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C22H30N3O4 400.2236; Found: 400.2235; mp 124.6-126.5
°C.
3-hexyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aha),
solid, 92 mg, isolated yield 74%; 1H NMR (700 MHz, CDCl3)
δ 8.84 (s, 1H), 7.13-7.17 (m, 2H), 6.79-6.83 (m, 2H), 4.43
(dd, J = 7.9, 1.4 Hz, 1H), 3.84-3.99 (m, 4H), 3.75 (s, 3H),
2.97 (dd, J = 16.4, 8.2 Hz, 1H), 2.86 (dd, J = 16.6, 1.3 Hz,
1H), 1.55-1.73 (m, 4H), 1.25-1.35 (m, 6 H), 0.95 (t, J = 7.4
Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (176 MHz,
CDCl3) δ 171.6, 160.7, 158.3, 150.3, 143.2, 133.0, 127.1,
113.9, 92.7, 54.9, 43.8, 41.5, 37.3, 32.7, 31.1, 27.2, 26.2,
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113.9, 92.0, 54.9, 43.0, 37.0, 33.0, 20.6, 11.0; IR νmax
:
2961.3, 1699.4, 1638.3, 1485.1, 1241.9, 1178.4, 1029.4,
831.4, 751.9, 685.9, 520.4 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C23H24N3O4 406.1767; Found: 406.1770;
mp 94.9-102.3 °C.
3-ethyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aca),
solid, 78 mg, isolated yield 73%; 1H NMR (400 MHz, CDCl3)
δ 8.83 (s, 1H), 7.15-7.20 (m, 2H), 6.80-6.86 (m, 2H), 4.46
(dd, J = 7.7, 1.3 Hz, 2H), 3.90-4.07 (m, 4H), 3.78 (s, 3H),
2.99 (dd, J=16.4, 7.8 Hz, 1H), 2.88 (dd, J = 16.4, 1.5 Hz, 1H),
1.64-1.73 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.3
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 160.9,
158.8, 150.6, 143.6, 133.4, 127.5, 114.3, 93.2, 55.3, 44.2,
37.7, 37.0, 33.1, 22.2, 12.9, 10.8; IR νmax: 3234.5, 3190.7,
2965.0, 1688.8, 1642.4, 1508.2, 1462.4, 1346.1, 1299.6,
1234.6, 1179.7, 1028.0, 1014.0, 839.2, 742.3, 661.0,
523.2, 474.3 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C19H24N3O4 358.1767; Found: 358.1765; mp 80.9-83.7 °C.
3-butyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7ada),
solid, 71 mg, isolated yield 61%; 1H NMR (700 MHz, CDCl3)
δ 8.63 (d, J = 4.9 Hz, 1H), 7.14-7.17 (m, 2H), 6.80-6.83 (m,
2H), 4.43 (d, J = 6.7 Hz, 1H), 3.85-3.97 (m, 4H), 3.76 (s, 3H),
2.97 (dd, J = 16.3, 8.0 Hz, 1H), 2.86 (d, J = 15.7 Hz, 1H),
1.56-1.64 (m, 4H), 1.35 (sxt, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4
Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (176 MHz,
CDCl3) δ 171.4, 160.7, 158.4, 150.3, 143.2, 133.0, 127.1,
113.9, 92.7, 54.9, 43.8, 41.3, 37.3, 32.7, 29.4, 21.8, 19.8,
13.4, 10.4; IR νmax: 3171.5, 2959.1, 2930.8, 2872.1,
1683.6, 1636.1, 1509.2, 1475.1, 1438.0, 1355.2, 1330.7,
1296.3, 1249.9, 1234.7, 1175.5, 1147.8, 1087.2, 1031.8,
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22.2, 21.8, 13.6, 10.4; IR νmax: 3246.3, 2953.0, 2927.2,
(d, J = 7.10 Hz, 1H), 3.83-3.96 (m, 2H), 3.76 (s, 3H), 2.95
2
1690.1, 1637.3, 1508.9, 1465.6, 1353.0, 1299.5, 1239.0,
1176.2, 1033.4, 833.4, 754.2, 735.9, 664.9, 557.4, 510.3
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C23H32N3O4
414.2393; Found: 414.2390; mp 131.9-134.7 °C.
(dd, J = 8.00, 16.60 Hz, 1H), 2.85 (d, J = 15.38 Hz, 1H), 1.59-
1.64 (m, 2H), 0.93 (t, J = 7.42 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 172.5, 161.2, 158.8, 150.9, 144.0, 137.0,
133.3, 129.0, 128.4, 127.6, 127.5, 114.3, 93.1, 55.3, 44.9,
44.4, 37.8, 33.1, 22.1, 10.7; IR νmax: 3244.0, 2965.1,
2934.1, 1688.0, 1634.7, 1506.8, 1472.9, 1454.4, 1436.5,
1360.9, 1306.0, 1237.4, 1180.2, 1031.9, 828.3, 745.0,
694.4, 598.4, 550.7, 523.2, 494.7, 461.0 cm-1; HRMS (ESI-
TOF) (M+H)+ m/z: Calcd for C24H26N3O4 420.1923; Found:
420.1923; mp 164.9-177.1 °C.
3-benzyl-5-(4-methoxyphenyl)-1-phenyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7abc),
solid, 98 mg, isolated yield 72%; 1H NMR (400 MHz, CDCl3)
δ 7.57-7.64 (m, 3H), 7.50-7.56 (m, 2H), 7.29-7.36 (m, 5H),
7.22-7.26 (m, 2H), 6.84-6.90 (m, 2H), 6.79 (s, 1H), 5.14
(dd, J = 21.0, 13.4 Hz, 3H), 4.51 (dd, J = 7.8, 1.2 Hz, 2H),
3.80 (s, 3H), 3.00 (dd, J = 16.6, 7.8 Hz, 2H), 2.87 (dd, J =
16.3, 0.7 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.4,
161.2, 158.9, 150.6, 143.1, 136.8, 133.7, 132.2, 130.9,
130.9, 130.8, 129.6, 129.3, 129.0, 128.4, 127.7, 127.6,
114.4, 55.3, 44.9, 37.5, 33.5; IR νmax: 2928.5, 1700.2,
1637.0, 1484.3, 1239.2, 1141.9, 1029.5, 938.6, 832.6,
746.3, 685.5 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C27H24N3O4 454.1767; Found: 454.1769; mp 93.1-98.9 °C.
3-allyl-1-benzyl-5-(4-methoxyphenyl)-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7ajb),
solid 73 mg, isolated yield 58%; 1H NMR (700 MHz, CDCl3)
δ 8.00 (s, 1 H), 7.36-7.40 (m, 2H), 7.33-7.36 (m, 1H),
7.20-7.24 (m, 2H), 7.07-7.11 (m, 2H), 6.77-6.80 (m, 2H),
5.91 (ddt, J = 17.1, 10.2, 5.8, 5.8 Hz, 1H), 5.44 (d, J = 17.0
Hz, 1H), 5.27 (dq, J = 17.1, 1.4 Hz, 1H), 5.20 (dq, J = 10.3,
1.2 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 4.60 (ddt, J = 18.3,
5.8, 1.4, 1.4 Hz, 2H), 4.41 (dd, J = 8.0, 1.5 Hz, 1H),
3.74-3.76 (m, 3H), 2.90 (dd, J = 16.3, 8.0 Hz, 1H), 2.79 (dd,
J = 16.3, 1.5 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ
170.2, 160.3, 158.4, 150.6, 143.8, 133.9, 132.8, 131.3,
129.6, 129.2, 128.3, 127.1, 125.8, 117.7, 113.9, 54.9, 45.7,
43.6, 37.3, 33.0; IR νmax: 3236.9, 3182.4, 1689.9, 1631.7,
1509.6, 1452.5, 1349.4, 1299.4, 1246.9, 1185.8, 1154.0,
1032.9, 933.5, 722.9, 692.5, 589.6, 522.0 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C24H24N3O4 418.1767; Found:
418.1765; mp 143.6-145.9 °C.
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3-heptyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aia),
1
solid, 111 mg, isolated yield 87%; H NMR (700 MHz,
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CDCl3) δ 8.92 (s, 1H), 7.13-7.17 (m, 2H), 6.79-6.83 (m, 2H),
4.43 (dd, J = 7.9, 1.4 Hz, 1H), 3.86-3.99 (m, 4H), 3.75 (s,
3H), 2.97 (dd, J = 16.6, 8.0 Hz, 1H), 2.86 (dd, J = 16.5, 1.2
Hz, 1H), 1.56-1.67 (m, 4H), 1.21-1.34 (m, 8H), 0.95 (t, J =
7.4 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (176 MHz,
CDCl3) δ 171.7, 160.7, 158.4, 150.3, 143.2, 133.0, 127.1,
113.9, 92.7, 54.9, 43.8, 41.5, 37.3, 32.8, 31.8, 28.6, 27.3,
26.5, 22.2, 21.8, 13.7, 10.4; IR νmax: 3234.1, 3184.0,
2963.2, 2927.4, 2854.5, 1686.7, 1633.6, 1510.2, 1472.7,
1348.2, 1294.0, 1239.4, 1180.7, 1034.4, 826.3, 781.4,
756.4, 738.2, 485.0 cm-1; HRMS (ESI-TOF): (M+H)+ Calcd
for C24H34N3O4 428.2549; Found: 428.2550; mp 129.9-
131.6 °C.
3-allyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aja),
solid, 80 mg; isolated yield 69%; 1H NMR (700 MHz, CDCl3)
δ 8.43 (s, 1H), 7.13-7.17 (m, 2H), 6.80-6.83 (m, 2H),
5.82-5.91 (m, 1H), 5.24 (dq, J = 17.1, 1.4 Hz, 1H), 5.17 (dq,
J = 10.2, 1.3 Hz, 1H), 4.54 (ddt, J = 19.7, 5.9, 1.3, 1.3 Hz,
2H), 4.44 (dd, J = 7.9, 1.4 Hz, 1H), 3.91 (m, J = 18.7, 9.7,
5.8 Hz, 2H), 3.76 (s, 3H), 2.97 (dd, J = 16.4, 8.0 Hz, 1H),
2.87 (dd, J = 16.5, 1.0 Hz, 1H), 1.62-1.74 (m, 2H), 0.97 (t, J
= 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 171.1,
160.4, 158.4, 150.1, 143.3, 132.9, 131.4, 127.1, 117.6,
113.9, 92.7, 54.9, 43.9, 43.4, 37.2, 32.7, 21.7, 10.5; IR νmax
:
3171.5, 2936.3, 1688.1, 1651.3, 1509.0, 1464.7, 1348.0,
1303.2, 1237.4, 1174.2, 1031.4, 934.6, 831.6, 778.3,
758.0, 686.9, 557.1, 518.2, 461.1 cm-1; HRMS (ESI-TOF):
(M+H)+ Calcd for C20H24N3O4 370.1767; Found: 370.1766;
mp 137.6-140.0 °C.
5-(4-methoxyphenyl)-3-(2-methylallyl)-1-propyl-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
(7aka), solid 90 mg, isolated yield 79%; 1H NMR (700 MHz,
CDCl3) δ 8.76 (s, 1H), 7.13-7.17 (m, 2H), 6.79-6.82 (m, 2H),
4.82-4.84 (m, 1H), 4.65 (s, 1H), 4.46-4.52 (m, 2H), 3.94-
4.01 (m, 1H), 3.87-3.93 (m, 1H), 3.75 (s, 3H), 2.99 (dd, J =
16.6, 8.0 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 1.75 (d, J = 0.4
Hz, 3H), 1.62-1.73 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (176 MHz, CDCl3) δ 172.1, 160.6, 158.4, 150.3,
143.6, 139.2, 132.9, 127.1, 113.9, 110.0, 92.6, 54.9, 46.0,
43.9, 37.4, 32.6, 21.7, 20.2, 10.3; IR νmax: 3165.12965.4,
2936.3, 1683.8, 1639.4, 1508.3, 1478.2, 1436.4, 1354.4,
1296.9, 1249.5, 1232.4, 1174.4, 1148.5, 1032.4, 906.4,
839.2, 779.3, 753.4, 659.2, 528.9 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C21H26N3O4 384.1923; Found:
384.1923; 154.4-156.6 °C.
1,3-dibenzyl-5-(4-methoxyphenyl)-5,8-dihydropyrido-
[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7abb), solid,
1
112 mg, isolated yield 80%; H NMR (700 MHz, CDCl3) δ
7.48-7.50 (m, 3H), 7.38-7.42 (m, 2H), 7.36 (d, J = 7.5 Hz,
1H), 7.29-7.33 (m, 2H), 7.26-7.29 (m, 1H), 7.21-7.24 (m,
2H), 7.07-7.10 (m, 2H), 6.76-6.80 (m, 2H), 5.50 (d, J = 16.8
Hz, 1H), 5.19 (d, J = 13.8 Hz, 1H), 5.13 (d, J = 13.8 Hz, 1H),
4.91-4.97 (m, 1H), 4.42 (dd, J = 8.0, 1.5 Hz, 1H), 3.75 (s,
3H), 2.89 (dd, J = 16.3, 8.0 Hz, 1H), 2.78 (dd, J = 16.3, 1.5
Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.8, 160.6,
158.4, 151.0, 143.8, 136.4, 133.8, 132.8, 129.3, 128.7,
128.4, 128.1, 127.3, 127.1, 125.7, 114.0, 93.3, 54.9, 45.9,
44.7, 37.3, 33.1; IR νmax: 1693.6, 1626.6, 1505.6, 1454.0,
1435.1, 1351.9, 1295.8, 1231.1, 1177.3, 1147.3, 1029.5,
830.2, 730.4, 696.6, 602.5, 525.7, 490.6 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C28H26N3O4 468.1923; Found:
468.1922; mp 93.4-100.2 °C.
3-benzyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydro-
pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aba),
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solid, 113 mg, isolated yield 90%; H NMR (700 MHz,
CDCl3) δ 8.73 (s, 1H), 7.45 (d, J = 7.10 Hz, 2H), 7.27-7.32
(m, 2H), 7.22-7.25 (m, 1H), 7.15 (d, J = 8.60 Hz, 2H), 6.81
(d, J = 8.71 Hz, 2H), 5.11 (dd, J = 13.70, 20.40 Hz, 2H), 4.44
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1-benzyl-5-(4-methoxyphenyl)-3-(2-methylbenzyl)-5,8-
24.0; IR νmax: 2957.8, 1694.3, 1628.9, 1506.6, 1459.9,
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
(7alb), solid, 62 mg, isolated yield 43%; 1H NMR (700 MHz,
CDCl3) δ 8.38 (s, 1H), 7.30-7.36 (m, 3H), 7.09-7.19 (m, 7H),
7.03 (d, J = 7.3 Hz, 1H), 6.76-6.83 (m, 2H), 5.34 (d, J = 16.6
Hz, 1H), 5.12-5.23 (m, 3H), 4.44 (d, J = 6.7 Hz, 1H), 3.76 (s,
3H), 2.91 (dd, J = 16.5, 7.9 Hz, 1H), 2.76-2.84 (m, 1H), 2.42
(s, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 170.5, 160.7,
158.4, 151.0, 144.0, 135.5, 134.2, 134.1, 132.7, 130.0,
129.1, 128.2, 127.1, 126.8, 125.8, 125.6, 125.5, 114.1,
93.2, 54.9, 45.6, 42.2, 37.3, 33.0, 19.0; IR νmax: 3235.8,
3176.8, 1684.1, 1643.2, 1508.4, 1460.7, 1301.5, 1247.5,
1230.6, 117.0, 1147.7, 1028.5, 833.1, 739.6, 700.4, 473.6
cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C29H28N3O4
482.2080; Found: 482.2079; mp 198.9-203.2 °C.
1352.1, 1294.7, 1231.9, 1178.0, 1147.0, 1031.0, 830.5,
780.9, 730.4, 697.1, 526.6 cm-1; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C31H32N3O4 510.2393; Found: 510.2392;
mp 93.1-96.5 °C.
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1-benzyl-3-(3-methoxybenzyl)-5-(4-methoxyphenyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
1
(7apb), solid, 115 mg, isolated yield 77%; H NMR (400
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MHz, CDCl3) δ 7.37-7.45 (m, 4H), 7.22-7.27 (m, 3H), 7.03-
7.13 (m, 4H), 6.78-6.86 (m, 3H), 5.52 (d, J = 16.9 Hz, 1H),
5.12-5.22 (m, 2H), 4.95 (d, J = 16.9 Hz, 1H), 4.44 (dd, J =
7.7, 1.6 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.92 (dd, J = 16.6,
7.6 Hz, 1H), 2.81 (dd, J = 16.6, 1.0 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 170.1, 160.9, 159.7, 158.8, 151.4,
144.2, 138.3, 134.2, 133.2, 129.7, 129.4, 128.8, 127.5,
126.1, 121.2, 114.4, 114.2, 113.4, 93.7, 55.3, 55.2, 46.3,
45.0, 37.7, 33.5; IR νmax: 1694.3, 1632.8, 1506.6, 1454.4,
1351.2, 1286.8, 1232.4, 1148.3, 1032.1, 953.8, 831.4,
780.6, 757.3, 730.8, 694.8, 526.1, 481.6 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C29H28N3O5 498.2029; Found:
498.2031; 82.5-86.8 °C.
1-benzyl-5-(4-methoxyphenyl)-3-(3-methylbenzyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
1
(7amb), solid, 62 mg, isolated yield 43%; H NMR (700
MHz, CDCl3) δ 7.75 (s, 1H), 7.33-7.39 (m, 3H), 7.26-7.29
(m, 2H), 7.18-7.23 (m, 3H), 7.06-7.11 (m, 3H), 6.76-6.80
(m, 2H), 5.46 (d,
J = 16.8 Hz, 1H), 5.15 (d,
J = 14.0 Hz, 1H), 5.11 (d, J = 13.8 Hz, 1H), 5.00 (d, J = 16.8
Hz, 1H), 4.42 (dd, J = 7.7, 1.3 Hz, 1H), 3.75 (s, 3H), 2.89 (dd,
J = 16.5, 7.9 Hz, 1H), 2.78 (dd, J = 16.6, 1.3 Hz, 1H), 2.32
(s, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.8, 160.6,
158.4, 151.0, 143.8, 137.7, 136.3, 133.8, 132.8, 129.3,
129.2, 128.4, 128.1, 128.0, 127.1, 125.7, 125.6, 113.9,
93.3, 54.9, 45.9, 44.7, 37.3, 33.1, 21.0; IR νmax: 1693.6,
1621.5, 1505.8, 1454.6, 1435.1, 1350.0, 1296.9, 1230.6,
1177.4, 1147.1, 1030.3, 830.8, 780.0, 755.7, 729.6, 695.8,
525.6, 467.4 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C29H28N3O4 482.2080; Found: 482.2079; mp 82.2-85.5 °C.
1-benzyl-5-(4-methoxyphenyl)-3-(4-methylbenzyl)-5,8-
dihydropyrido[2,3-d]pyrimidine--2,4,7(1H,3H,6H)-trione
1-benzyl-3-(2-fluorobenzyl)-5-(4-methoxyphenyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
1
(7aqb), solid, 91 mg, isolated yield 62%; H NMR (400
MHz, CDCl3) δ 7.58 (s, 1H), 7.35-7.47 (m, 3H), 7.21-7.33
(m, 6H), 7.02-7.16 (m, 4H), 6.76-6.85 (m, 2H), 5.49 (d, J =
16.6 Hz, 1H), 5.29 (dd, J = 17.6, 14.7 Hz, 2H), 5.01 (d, J =
16.6 Hz, 1H), 4.45 (dd, J = 7.7, 1.6 Hz, 1H), 3.77 (s, 3H),
2.94 (dd, J = 16.4, 7.8 Hz, 1H), 2.82 (dd, J = 16.4, 1.0 Hz,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 162.0, 160.9,
159.6, 158.8, 151.2, 144.4, 134.3, 133.1, 129.6, 129.4 (d,
J = 4.0 Hz), 129.1 (d, J = 7.9 Hz), 128.7, 127.5, 126.2, 124.1
(d, J = 3.2 Hz), 123.7 (d, J = 14.3 Hz), 115.5 (d, J = 21.5 Hz),
114.4, 93.6, 55.3, 46.2, 37.7, 33.4; IR νmax: 2834.9, 1694.6,
1627.3, 1505.2, 1493.2, 1454.2, 1351.8, 1296.4, 1228.6,
1177.2, 1147.2, 1094.1, 1030.5, 831.3, 751.2, 729.6,
696.5, 654.7, 525.9, 507.4, 432.3 cm-1; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C28H25FN3O4 486.1829; Found:
486.1828; mp 84.1-90.9 °C.
1
(7anb), solid, 50 mg, isolated yield 34%; H NMR (700
MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz, 2H), 7.29-7.33 (m, 4H),
7.16 (dd, J = 7.2, 2.3 Hz, 2H), 7.07-7.12 (m, 4H), 6.76-6.79
(m, 2H), 5.09-5.15 (m, 5H), 4.39 (dd, J = 7.7, 1.3 Hz, 1H),
3.74 (s, 3H), 2.83 (dd, J = 16.4, 8.0 Hz, 1H), 2.74 (dd, J =
16.4, 1.7 Hz, 1H), 2.31 (s, 3H); 13C{1H} NMR (101MHz,
CDCl3) δ 170.1, 161.0, 158.8, 151.4, 144.2, 137.4, 134.3,
133.9, 133.2, 129.7, 129.1, 129.1, 128.8, 127.5, 126.1,
1-benzyl-3-(3-fluorobenzyl)-5-(4-methoxyphenyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
1
(7arb), solid, 109 mg, isolated yield 75%; H NMR (400
114.4, 93.7, 55.3, 46.3, 44.9, 37.7, 33.5, 21.2; IR νmax
:
MHz, CDCl3) δ 7.93 (s, 1H), 7.34-7.44 (m, 3H), 7.16-7.33
(m, 5H), 7.07-7.15 (m, 2H), 6.92-7.03 (m, 1H), 6.77-6.86
1693.6, 1621.6, 1506.4, 1453.3, 1435.5, 1351.6, 1296.8,
1232.7, 1178.7, 1148.0, 1029.8, 831.2, 782.1, 729.7,
697.0, 526.0, 472.9 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C29H28N3O4 482.2080; Found: 482.2080; mp
72.1-79.6 °C.
(m, 2H), 5.45 (d,
J = 16.6 Hz, 1H), 5.17 (dd,
J = 23.0, 13.9 Hz, 2H), 5.06 (d, J = 16.6 Hz, 1H), 4.44 (dd, J
= 7.7, 1.6 Hz, 1H), 3.77 (s, 3H), 2.92 (dd, J = 16.4, 7.8 Hz,
1H), 2.81 (dd, J = 16.4, 1.7 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 170.3, 164.0, 161.2 (d, J=75.5 Hz), 158.9, 151.3,
144.4, 139.2 (d, J=7.9 Hz), 134.2, 133.1, 129.9 (d, J=8.7
Hz), 129.7, 128.8, 127.5, 126.1, 124.6, 115.8 (d, J=22.3
Hz), 114.6 (d, J=21.5 Hz), 114.4, 93.7, 55.3, 46.3, 44.6,
37.7, 33.5; IR νmax: 3148.5, 3058.8, 3005.0, 2955.0,
2836.6, 1686.5, 1632.4, 1508.8, 1462.3, 1439.7, 1359.0,
1309.5, 1241.9, 1184.5, 1153.5, 1137.5, 1026.5, 965.5,
948.8, 832.9, 781.2, 755.5, 689.1, 519.4, 486.7 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C28H25FN3O4
486.1829; Found: 486.1829; mp 173.3-174.5 °C.
1-benzyl-3-(4-isopropylbenzyl)-5-(4-methoxyphenyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
1
(7aob), solid, 105 mg, isolated yield 69%; H NMR (400
MHz, CDCl3) δ 7.34-7.52 (m, 6H), 7.25 (d, J = 7.6 Hz, 2H),
7.19 (d, J = 8.1 Hz, 2H), 7.08-7.15 (m, 2H), 6.77 - 6.83 (m,
2H), 5.52 (d, J=16.9 Hz, 1 H), 5.19 (d, J = 13.7 Hz, 1 H), 5.12
(d, J = 13.7 Hz, 1H), 4.94 (d, J=16.9 Hz, 1H), 4.44 (d, J = 5.9
Hz, 1H), 3.77 (s, 3H), 2.91 (dd, J = 13.8, 6.7 Hz, 1H), 2.76-
2.84 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 170.3, 161.0, 158.8, 151.4, 148.3, 144.2,
134.3, 134.2, 133.2, 129.6, 129.2, 128.7, 127.5, 126.5,
126.2, 114.4, 93.8, 55.3, 46.2, 44.9, 37.7, 33.8, 33.5, 24.0,
1-benzyl-3-(3-bromobenzyl)-5-(4-methoxyphenyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
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(7asb), solid, 95 mg, isolated yield 58%; H NMR (400
MHz, CDCl3) δ 7.81 (s, 1H), 7.63 (t, J=1.7 Hz, 1H), 7.35-7.46
(m, 5H), 7.16-7.26 (m, 3H), 7.07-7.14 (m, 2H), 6.77-6.86
(m, 2H), 5.46 (d, J = 16.9 Hz, 1H), 5.14 (dd, J = 22.0, 13.9
Hz, 2H), 5.04 (d, J = 16.6 Hz, 1H), 4.44 (d, J = 6.1 Hz, 1H),
3.77 (s, 3H), 2.93 (dd, J = 16.4, 7.8 Hz, 1H), 2.81 (dd, J =
16.4, 1.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1,
160.8, 158.9, 151.3, 144.4, 139.0, 134.2, 133.1, 131.8,
130.9, 130.0, 129.7, 128.8, 127.7, 127.4, 126.1, 122.5,
114.4, 93.7, 55.3, 46.3, 44.5, 37.6, 33.5; IR νmax: 3156.6,
2961.8, 2833.7, 1686.5, 1633.2, 1509.8, 1459.2, 1439.2,
1357.5, 1231.6, 1177.1, 1035.4, 779.3, 756.1, 695.5,
668.2, 650.1, 479.0 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C28H25BrN3O4 546.1028; Found: 546.1031; mp
197.6-200.0 °C.
δ 7.03-7.07 (m, 2H), 6.79-6.83 (m, 2H), 4.54 (s, 1H), 4.19
(d, J = 5.0 Hz, 1H), 3.77-3.93 (m, 4H), 3.76 (s, 3H), 3.29 (d,
J = 12.0 Hz, 1H), 3.13 (dt, J = 2.5, 12.3 Hz, 1H), 1.97 (tt, J =
5.0, 13.0 Hz, 1H), 1.87 (dd, J = 2.3, 13.0 Hz, 1H), 1.73 (sxt,
J = 7.6 Hz, 2H), 1.59 - 1.66 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H),
0.88 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)
161.5, 158.0, 151.4, 148.9, 137.7, 128.4, 113.8, 85.6, 55.3,
2
3
4
5
6
7
8
9
43.3, 42.7, 37.5, 34.4, 28.8, 21.6, 21.3, 11.4, 11.2; IR νmax
:
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12
13
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16
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3301.0, 2960.2, 2932.8, 2873.3, 1685.9, 1590.3, 1538.2,
1507.9, 1443.3, 1347.7, 1336.0, 1264.4, 1241.4, 1170.1,
1032.4, 831.6, 770.3, 757.8, 549.7, 532.4, 485.6 cm-1;
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C20H28N3O3
358.2131; Found: 358.2131; mp 69.3-81.4 °C.
5-(4-methoxyphenyl)-2,4-dioxo-1,3-dipropyl-7-(pyridin-1-
ium-1-yl)-1,2,3,4,6,7-hexahydro-pyrido[2,3-d]pyrimidin-
7-ide (10), to the solution of 7aaa (1 mmol; 0,37 g) in
pyridine (1 mL) tosyl chloride (1.1 mmol; 0.21 g) was
added at temperature 0 °C. The reaction was then
continued at room temperature for 24 h. After the
addition of 5 mL of water, the product was extracted with
ethyl acetate. The crude product was purified by flash
chromatography using gradient elution (0-100%
AcOEt in hexanes). Expected compound was obtained
as solid (86 mg) with 20% yield; 1H NMR (700 MHz, CDCl3)
δ 7.25-7.22 (m, 2H), 7.10 (s, 2H), 6.96-6.93 (m, 2H), 6.37
(s, 1H), 5.08 (dtd, J = 1.1, 3.6, 7.4 Hz, 2H), 4.29-4.25 (m,
2H), 3.91-3.87 (m, 2H), 3.85-3.84 (m, 3H), 2.99 (tt, J = 1.7,
3.6 Hz, 2H), 1.80 (tsxt, J = 1.8, 7.4 Hz, 2H), 1.62 (tsxt, J =
2.1, 7.5 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.5 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 159.5, 155.8,
152.3, 151.7, 151.3, 132.3, 129.3, 123.7, 113.2, 107.3,
104.9, 100.8, 55.2, 44.6, 43.0, 23.2, 21.2, 21.1, 11.5, 11.3;
IR νmax: 2958.3, 1703.4, 1656.8, 1582.8, 1544.2, 1514.1,
1426.3, 1390.3, 1361.6, 1260.2, 1236.3, 1179.2, 1105.6,
1086.4, 1026.9, 969.3, 957.8, 893.1, 820.5, 755.8, 735.4,
705.7, 676.8, 574.9, 562.4, 488.5, 453.8 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C25H29N4O3 433.2240; Found:
433.2243; mp 76.6-83.8 °C.
5-(4-methoxyphenyl)-2,4-dioxo-1,3-dipropyl-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidin-7-yl 4-methylbenzene-
sulfonate (11), to the solution of 7aaa (0.5 mmol; 0,19 g)
in DIPEA (1 mL) and DCM (1 mL) tosyl chloride (0.55
mmol; 0.10 g) was added at temperature 0 °C. The
reaction was then continued at room temperature for
24 h. After the addition of 5 mL of water, the product was
extracted with DCM. The crude product was purified by
flash chromatography using gradient elution (0-100%
AcOEt in hexanes). Expected compound was obtained
as solid (91 mg) with 35% yield; 1H NMR (700 MHz, CDCl3)
δ 7.92-7.89 (m, 2H), 7.41-7.37 (m, 2H), 7.24-7.21 (m, 2H),
6.96-6.93 (m, 2 H), 6.70 (s, 1H), 4.03-3.99 (m, 2H), 3.91-
3.87 (m, 2H), 3.85 (s, 4H), 2.47 (s, 3H), 1.61-1.57 (m, 4H),
0.90-0.87 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.7,
159.1, 158.9, 157.4, 151.0, 150.1, 145.3, 133.7, 129.9,
129.5, 129.1, 127.8, 113.0, 111.9, 106.2, 54.8, 44.4, 43.0,
21.4, 20.5, 20.5, 10.8, 10.7; IR νmax: 2961.6, 2932.6,
2874.3, 1713.0, 1664.7, 1580.4, 1555.5, 1514.4, 1457.7,
1378.8, 1339.4, 1247.1, 1222.7, 1193.8, 1177.2, 1156.5,
1088.8, 1031.8, 946.3, 904.5, 830.4, 804.1, 754.5, 721.1,
1-benzyl-5-(4-methoxyphenyl)-3-(3-(trifluoromethyl)-
benzyl)--5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7-
(1H,3H,6H)-trione (7atb), solid, 139 mg, isolated yield
87%; 1H NMR (700 MHz, CDCl3) δ 7.72 (s, 1H), 7.67 (d, J =
7.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.34-7.47
(m, 4H), 7.20-7.25 (m, 2H), 7.07-7.11 (m, 2H), 6.75-6.82
(m, 2H), 5.48 (d, J = 16.8 Hz, 1H), 5.21 (dd, J = 25.2, 14.0
Hz, 2H), 4.97 (d, J = 16.6 Hz, 1H), 4.43 (dd, J = 7.9, 1.4 Hz,
1H), 3.75 (s, 3H), 2.92 (dd, J = 16.6, 8.0 Hz, 1H), 2.81 (dd,
J = 16.5, 1.4 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ
169.4, 160.4, 158.5, 150.9, 144.0, 137.3, 133.6, 132.6,
132.2, 129.4, 128.6, 128.5, 127.0, 125.7, 125.2 (q, J = 4.1
Hz), 124.2 (q, J = 3.7 Hz), 114.0, 93.2, 54.9, 46.0, 44.2,
37.2, 33.0; IR νmax: 1693.8, 1629.9, 1506.1, 1453.0,
1325.5, 1233.6, 1158.4, 1116.3, 1072.4, 1030.6, 830.9,
781.4, 730.0, 698.8, 657.0, 525.6, 477.5 cm-1; HRMS (ESI-
TOF) m/z: (M+H): Calcd for C29H25F3N3O4 536.1797;
Found: 536.1797; mp : 78.7-86.4 °C.
1-benzyl-5-(4-methoxyphenyl)-3-(4-nitrobenzyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
(7aub), solid, 44 mg, isolated yield 29%; H NMR (700
1
MHz, CDCl3) δ 7.64-7.61 (m, 2H), 7.54 (s, 1H), 7.43-7.36
(m, 4 H), 7.24-7.20 (m, 2H), 7.10-7.05 (m, 2H), 6.82-6.77
(m, 2H), 5.50 (d, J = 16.8 Hz, 1H), 5.23 (dd, J = 14.1, 36.0
Hz, 2H), 4.96 (d, J = 16.7 Hz, 1H), 4.41 (dd, J = 1.3, 7.9 Hz,
1H), 3.76 (s, 3H), 2.92 (dd, J = 8.0, 16.5 Hz, 1H), 2.80 (dd,
J = 1.3, 16.5 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ
169.3, 160.3, 158.5, 150.9, 147.1, 144.2, 143.5, 133.4,
132.6, 129.5, 129.4, 128.7, 127.0, 125.7, 123.3, 114.0,
93.2, 54.9, 46.1, 44.1, 37.2, 33.2; IR νmax: 1693.7, 1620.2,
1508.9, 1341.6, 1292.0, 1229.4, 1175.4, 1147.6, 1109.6,
1030.9, 834.3, 807.5, 696.0, 527.4, 507.7 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C28H25N4O6 513.1774; Found:
513.1772; mp 150.7-159.2 °C.
5-(4-methoxyphenyl)-1,3-dipropyl-5,6,7,8-tetrahydro-
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (9), solution of
7aaa (0.5 mmol; 0.19 g) in THF (5 mL) was added slowly
to the solution of LiAlH4 (0.5 mL; 1 mol/L) cooled down to
the temperature 0 °C. The reaction was carried out at the
same temperature for 24 h. The reaction mixture was
diluted with ethyl acetate (10 mL) and precipitated solid
was filtered off. The crude product was purified by flash
chromatography using gradient elution (0-100%
AcOEt in hexanes). Expected product was obtained as
solid (194 mg) with 72% yield; 1H NMR (700 MHz, CDCl3)
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665.2, 577.2, 546.1 cm-1; HRMS (ESI-TOF) m/z: (M+H)+
The Supporting Information is available free of
charge on the ACS Publications website at DOI:
NMR & IR spectra
Calcd for C27H30N3O6S 524.1855; Found: 524.1855; mp
76.6-83.8 °C.
3
4
5
7-(benzyloxy)-5-(4-methoxyphenyl)-1,3-dipropyl-5,6-
dihydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (12),
7aaa (0.25 mmol; 93 mg), benzyl bromide (1.25 mmol;
149 µL) and potassium carbonate (1.25 mmol; 0.16 g)
were mixed in anhydrous DMF (1 mL) at 80 °C (oil bath)
for 24 h. The reaction mixture was diluted with water (5
mL) and the product was extracted with ethyl acetate.
The crude product was purified by flash chromatography
using gradient elution (0-100% AcOEt in hexanes).
Expected compound was obtained as solid (73 mg) with
63% yield; 1H NMR (700 MHz, CDCl3) δ 7.39-7.31 (m, 5H),
7.04-7.01 (m, 2H), 6.77-6.74 (m, 2H), 5.41 (d, J = 13.4 Hz,
1H), 5.36 (d, J = 12.3 Hz, 1H), 4.26 (d, J = 9.3 Hz, 1H), 4.11-
4.06 (m, 1 H), 4.04-3.99 (m, 1H), 3.88 (ddd, J = 3.8, 6.5, 8.7
Hz, 2H), 3.75 (s, 3H), 2.89 (dd, J = 9.4, 16.8 Hz, 1H), 2.75
(dd, J = 1.0, 16.8 Hz, 1H), 1.71-1.61 (m, 4H), 0.95-0.89 (m,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 162.2, 158.6,
151.6, 150.7, 135.3, 134.1, 128.7, 128.5, 127.8, 127.6,
114.1, 95.5, 69.5, 55.2, 44.7, 43.0, 33.4, 33.4, 22.3, 21.0,
11.4, 11.3; IR νmax: 2962.7, 2934.6, 2875.5, 1696.3,
1640.6, 1587.8, 1508.9, 1460.3, 1398.5, 1389.7, 1339.8,
1272.6, 1243.0, 1222.7, 1174.7, 1099.4, 1033.2, 1024.0,
951.8, 909.5, 892.6, 830.5, 785.7, 750.6, 697.9, 594.5,
559.2, 527.7 cm-1; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C27H32N3O4 462.2393; Found: 462.2392; mp 99.4-106.6
°C.
6
7
8
9
ACKNOWLEDGEMENTS
We thank the National Science Center
UMO-2016/22/E/ST5/00469 for financial support.
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V. Nair, Recent advances in N-heterocyclic carbene
(NHC)-catalysed benzoin reactions, Beilstein J. Org. Chem.
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Carbene Catalysis in Total Synthesis, Angew. Chem. Int.
7-(benzyloxy)-5-(4-methoxyphenyl)-1,3-dipropyl-
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13),
7aaa (0.25 mmol; 93 mg), benzyl chloride (1.25 mmol;
144 µL) and potassium carbonate (1.25 mmol; 0.16 g)
were mixed in anhydrous DMF (1 mL) at 80 °C (oil bath)
for 24 h. The reaction mixture was diluted with water (5
mL) and the product was extracted with ethyl acetate.
The crude product was purified by flash chromatography
using gradient elution (0-100% AcOEt in hexanes).
Expected compound was obtained as viscous oil (52 mg)
with 45% yield; 1H NMR (700 MHz, CDCl3) δ 7.45-7.42 (m,
2H), 7.41-7.38 (m, 2H), 7.36-7.33 (m, 1H), 7.27-7.23 (m,
2H), 6.97-6.93 (m, 2H), 6.48 (s, 1H), 5.49 (s, 2H), 4.28-4.24
(m, 2H), 3.93-3.89 (m, 2H), 3.85 (s, 3H), 1.77-1.72 (m, 2H),
1.66-1.60 (m, 2H), 1.00 (t, J = 7.4 Hz, 2H), 0.90 (t, J = 7.5
Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 164.1, 159.6,
156.5, 150.6, 136.1, 131.1, 128.9, 128.2, 127.8, 127.1,
113.1, 112.8, 109.0, 101.8, 68.0, 44.4, 42.8, 20.9, 20.6,
11.1, 10.9; IR νmax: 3466.3, 2960.6, 2932.4, 2874.1,
1705.8, 1658.7, 1594.5, 1553.0, 1514.8, 1491.8, 1453.2,
1394.4, 1341.4, 1288.2, 1246.3, 1225.4, 1209.4, 1174.8,
1105.0, 1086.2, 1032.4, 1016.2, 996.0, 828.8, 803.4,
752.7, 731.4, 695.9, 670.9, 569.4, 526.0 cm-1; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C27H30N3O4 460.2236; Found:
460.2235.
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