Solid acid-catalyzed domino cyclization reaction: Regio- and diastereoselective synthesis of pyrido[2,3-: D] pyrimidine derivatives bearing three contiguous stereocenters

Article abstract of DOI:10.1039/c7gc03812g

An efficient and green domino approach for the synthesis of 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one derivatives using a recoverable carbonaceous material as a catalyst has been established. The new domino reaction was conducted by reacting the readily available and inexpensive starting materials 2,6-diaminopyrimidin-4(3H)-one, nitroolefin and aldehyde in water. A total of 24 examples were examined, and showed a broad substrate scope and high yields. The carbonaceous material catalyst can be reused at least 5 times without obvious deactivation. The proposed mechanism has explained the reaction process and the resulting high regio- and diastereoselectivities. The present green strategy shows attractive characteristics such as using water as a green medium, using an inexpensive and recoverable solid acid catalyst, and having a simple work-up/purification, without generating any waste products or using any metal promoters.

Full text of DOI:10.1039/c7gc03812g

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ARTICLE TYPE
Solid acid-catalyzed domino cyclization reaction: regio- and
diastereoselective synthesis of pyrido[2,3-d]pyrimidine derivatives
bearing three contiguous stereocenters
Furen Zhang,* Chunmei Li and Xuezheng Liang
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Efficient and green domino approach for the synthesis of 5,6,7,8ꢀtetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone derivatives using
recoverable carbonaceous material as catalyst has been established. The new domino reaction was conducted by reacting readily
available and inexpensive starting material of 2,6ꢀdiaminopyrimidinꢀ4(3H)ꢀone, nitroolefin and aldehyde in water. A total of 24 examples
were examined, and showed a broad substrate scope and high yields. The carbonaceous material catalyst can be reused at least 5 times
without obvious deactivation. A proposed mechanism has explained the reaction process and the resulting highly regioꢀ and
diastereoselectivity. The present green strategy shows attractive characteristics such as using water as green medium, inexpensive and
recoverable solid acid catalyst, simple workꢀup/purification and without generating any waste production or using any metal promoters.
1
0
Introduction
1
2
2
3
3
5
0
5
0
5
The construction of fiveꢀ or sixꢀmembered Nꢀcontaining
heterocycles, along with the creation of multiple stereogenic
centers, continues to be an appealing and demanding area of
research, and processes in which complex heterocyclic
compounds are synthesized in a oneꢀpot manner with high stereoꢀ
and regioselectivity are of growing interest in chemical sciences
because of the importance and prevalence of these motifs in many
1
biologically active natural products and drug molecules. Among
2
them, pyridopyrimidine, as an important structural motif, is
found in numerous substances that exhibits a broad range of
3
biological properties which includes antiꢀinflammatory,
4
5
6
7
antibacterial,
antitumor,
antiviral,
antimicrobial,
and
8
anticancer activities. Several representative examples of the
biologically active pyrido[2,3ꢀd]pyrimidine derivatives are shown
5
0
Fig.1 Example of bioactive pyrido[2,3ꢀd]pyrimidines.
2c
in Fig. 1. In view of their interesting properties, many efforts
have been devoted to efficient synthetic approaches to these
heterocycles. However, several crucial issues still remain in
regard to the limited substrate scopes, the use of transitionꢀmetal
catalyst and additives, use of hazardous or expensive reagents,
tedious workꢀup processes, the requirement of special apparatus,
especially, difficulty in recovery and reusability of the catalyst,
which adversely affect the economics as well as the environmentꢀ
friendly nature of the reaction. Thus, it remains highly desirable
to develop more environmentally benign synthetic methodologies
for construction of functionalized pyrido[2,3ꢀd]pyrimidine
molecules using easily accessible raw materials requiring milder
conditions as well as avoiding the need for toxic metal catalysts
and inaccessible starting materials.
5
6
6
5
0
5
Growing awareness of environmental concerns has led to
increased need for more environmentally acceptable processes in
the organic synthesis chemical industry. Heterogeneous catalysts
are known to be environmentally benign and have been widely
9
applied in advanced synthesis processes. As one of most
important heterogeneous catalysts, solid acid catalysts have
4
4
0
5
School of Chemistry and Chemical Engineering, Zhejiang Key
Laboratory of Alternative Technologies for Fine Chemicals Process,
Shaoxing University, Shaoxing, Zhejiang Province 312000, China. Fax:
inherent acid-base catalyzed activity, and advantageous for
10
product separation and reuse. Generally, good solid acid
catalysts for organic synthesis should have accessibility and good
dispersion of the active sites and thermal and chemical stability
during the reaction process and the separation stage. Since
8
6
(575) 88345682; Tel: 86 (575) 88345682; Eꢀmail:
frzhang@usx.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
11
Scharff firstly reported the solid acid carbonaceous materials,
tremendous successful investigations have been reported with
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DOI: 10.1039/C7GC03812G
1
2
wide variety of applications. In continuation of our ongoing
catalyzed by CꢀSO H (10 mg) was carried out in water at
3
o
research for the development of simple and efficient methods for 55 temperature ranging from room temperature to 100 C (entries 6,
1
3
heterocycle synthesis, herein, we wish to report a novel and
efficient oneꢀpot method for regioꢀ and diastereoselective
synthesis of 5,6,7,8ꢀtetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone
derivatives using recoverable carbonaceous material (CꢀSO H) as
catalyst in water. Desired aromatic or aliphatic substituents can 60 obviously. Thus, 70 C was chosen as the reaction temperature
21ꢀ24). As shown in Table 1, the yields of desired product 4a
were rise when the temperature was increased from room
o
5
temperature to 70 C. However, further increase of the
o
temperature to 100 C failed to improve the yield of product
3
o
be introduced to 5ꢀ and 7ꢀpositions of the pyrido[2,3ꢀ
d]pyrimidine skeleton through this domino reaction. Remarkably,
this convenient procedure generates three new CꢀC/N bond and
three contiguous stereogenic centers (Scheme 1).
for all further reactions.
a
Table 1 Optimization of reaction conditions
1
0
o
b
Entry
Catalyst (mg)
Solvent
T ( C)
Yield (%)
c
1
2
ꢀ
ꢀ
H
2
H
2
H
2
H
2
O
O
O
O
70
reflux
70
70
70
70
70
70
70
70
70
70
70
70
reflux
70
70
reflux
70
ꢀ
ꢀ
Scheme 1 Synthesis of 5,6,7,8ꢀtetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀ
one derivatives.
c
3
4
5
6
7
8
9
Amberlystꢀ15 (10)
Zeolite (HY) (10)
24
37
10
90
38
51
32
41
16
34
91
57
78
55
32
41
43
24
71
ꢀ
d
1
5
Results and discussion
Carbon (10)
H O
2
CꢀSO
HOAc (10)
TsOH (10)
3
H (10)
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
O
O
To begin our study, we chose 2,6ꢀdiaminopyrimidinꢀ4(3H)ꢀone
e
e
(
(
1a), (E)ꢀ(2ꢀnitrovinyl)benzene (2a) and 4ꢀmethylbenzaldehyde
3a) as model substrates to search for suitable reaction conditions.
e
PhCOOH (10)
e
1
1
1
0
1
2
CF
3
COOH (10)
The above model reaction was conducted to investigate the
impact of various reaction conditions on the reaction outcome,
including catalysts, solvents, temperature and so on. The results
are listed in Table 1.
e
HCl (10)
e
2
2
3
3
4
4
5
0
5
0
5
0
5
0
H
2
SO
CꢀSO H (20)
CꢀSO H (5)
4
(10)
13
3
1
1
1
1
4
5
6
7
3
CꢀSO
CꢀSO
CꢀSO
CꢀSO
CꢀSO
CꢀSO
CꢀSO
CꢀSO
CꢀSO
CꢀSO
3
3
3
3
3
3
3
3
3
3
H (10)
H (10)
H (10)
H (10)
H (10)
H (10)
H (10)
H (10)
H (10)
H (10)
MeOH
EtOH
DMF
THF
toluene
As shown in Table 1, the reaction did not proceed without
o
the acidic promoters, even at an enhanced temperature of 100 C
c
for 24 h (Table 1, entries 1ꢀ2). When zeolite (HY) and
Amberlystꢀ15 were used as catalyst in water, the reaction only
gave desired product with 24% and 37% yields, respectively
18
1
2
2
9
0
CH
2
Cl
O
O
O
O
2
reflux
50
rt
90
reflux
1
H
2
H
2
H
2
H
2
(entries 3ꢀ4). The carbonaceous material, which was obtained
c
2
2
c
from the single furaldehyde (carbon), showed very poor catalytic
activity because of little functionalities on the surface (entry 5).
23
91
90
2
4
a
However, the carbonaceous material (CꢀSO H) exhibited a
Reaction conditions: 1a (0.5 mmol), 2a (0.5mmol), 3a (0.5mmol),
b c
3
remarkably high activity for the formation of desired compound
catalysts ( x mg), solvent (3 mL), 8h. Isolated yields. The reaction
was carried out for 24 h. The carbonaceous material from the single
furaldehyde. 10 mol%
d
4
a (entry 6). Then, we screened different acids promoters for the
e
domino reaction using water as solvent. Unfortunately, when
various acidic catalysts such as HOAc, TsOH, PhCOOH and
CF COOH (entries 7ꢀ10), or with inorganic acids such as HCl
Under the above optimized conditions, the substrate scope of
3
and H SO (entries 11ꢀ12), were evaluated as potential promoters 65 this reaction was examined by using readily available starting
2
4
for the reaction, the desired product was obtained only in 16% to
8% yields. Next, the effect of catalyst loading on the reaction
materials. Satisfyingly, the reaction could proceed smoothly and
the desired products 4a-4r were isolated with highly regioꢀ and
diastereoselectivities (Table 2). First of all, various structurally
diverse nitroolefins were explored to react with 2,6ꢀ
3
was evaluated (entries 6, 13ꢀ14). The results revealed that
carbonaceous material (10 mg) was enough to promote the
reaction successfully. Further increasing the amount of catalyst to 70 diaminopyrimidinꢀ4(3H)ꢀone (1a) and 4ꢀmethylbenzaldehyde (3a)
2
0 mg did not obviously improve the yield. To further optimize
to establish the applicability of this protocol. Various functional
groups in nitroolefins were well tolerated and gave good to
excellent yields of desired product 4 (77%ꢀ90%) but with subtle
differences. Comparing to electronꢀdonating groups (i.e. 4ꢀMe
the reaction conditions, the solvent effect was then investigated,
various solvents, such as MeOH, EtOH, DMF, THF, toluene, and
dichloromethane were employed as reaction media. Among these
solvents, the protic solvents such as water, MeOH and EtOH 75 and 4ꢀOMe), nitroolefins having electronꢀneutral and electronꢀ
resulted in product 4a in higher isolated yields (entries 6, 15ꢀ16).
The strong protic solvent, water, gave highest (90%) yield. Other
two polar solvents, methanol and ethanol gave slightly lower
yields than that in water. A lower yield of product 4a was
withdrawing ones (i.e. 4ꢀH, 4ꢀF, 4ꢀCl, 4ꢀBr and 4ꢀNO ) gave the
2
products in relatively higher yields in this threeꢀcomponent
reaction. In addition, nitroolefins bearing 2ꢀsubstituted groups (i.e.
2ꢀCl and 2,4ꢀCl) gave relatively lower yields, which may be
obtained when the reaction was performed in different aprotic 80 attributed to the effect of steric hindrance. Additionally, when
solvent (entries 17ꢀ20). Subsequently, the same reaction
(E)ꢀ1ꢀ(2ꢀnitrovinyl)naphthalene was used, the reaction could be
2
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a
Table 2 Synthesis of 5,6,7,8ꢀtetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone
derivatives
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), Cꢀ
o b
a,b
3
SO H (10 mg), water (3 mL), 70 C, 8 h. Isolated yields.
5
0
5
0
5
0
carried out smoothly to give target product with 79% isolated
yield.
Then, as an extension of the above study, we chose a variety
of aldehydes 3 to react with 1a and 2a to investigate the
possibility of this reaction processes. Pleasingly, the reactions
proceeded smoothly to give corresponding 5,6,7,8ꢀ
tetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone derivatives in 72ꢀ
87% yields with very high stereoselectivities. As anticipated, both
1
1
2
2
3
O
NO2
HN
electronꢀneutral, electronꢀdeficient, such as 4ꢀBr and 4ꢀCF , and
3
H2N
N
N
H
i
electronꢀrich, such as 4ꢀ Pr and 4ꢀOMe, aromatic groups on
aldehydes showed very good isolated yields of 4qꢀ4r (80%ꢀ81%).
Similar to above, aldehydes bearing 2ꢀsubstituted groups (i.e. 2ꢀ
Br, 2,4ꢀCl and 2,6ꢀCl), gave relatively lower yields. Furthermore,
fused ring aromatic aldehyde, 1ꢀnaphthaldehyde, was also
converted into the corresponding 5,6,7,8ꢀtetrahydropyrido[2,3ꢀ
d]pyrimidinꢀ4(3H)ꢀone 4s in 76% yields. Less reactive
heteroaromatic aldehyde, thiopheneꢀ2ꢀcarbaldehyde, still
displayed high reactivity and led to the desired product 4w with
75% yield. Next, we used aliphatic aldehydes, such as 3ꢀ
methylbutanal, to replace the aromatic aldehydes. Fortunately, we
found that the reaction of 2,6ꢀdiaminopyrimidinꢀ4(3H)ꢀone, (E)ꢀ
(2ꢀnitrovinyl)benzene and 3ꢀmethylbutanal can occur smoothly in
above conditions to afford the corresponding 5,6,7,8ꢀ
tetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone in excellent yield
(86%). However, when aldehyde was replaced with isatin (3aa)
to react with 2,6ꢀdiaminopyrimidinꢀ4(3H)ꢀone (1a) and (E)ꢀ(2ꢀ
nitrovinyl)benzene (2a), no desired product (4aa) was given.
4
a, 90%
4
b, 87%
4c, 88%
NO2
O
NO2
HN
H2N
N
N
H
4
e, 85%
4
d, 87%
4f, 83%
OMe
O
NO2
HN
H2N
N
N
H
4
h, 80%
4
4
i, 77%
l, 83%
4
g, 82%
O
N
NO2
HN
Instead
intermediate
2,6ꢀdiaminoꢀ5ꢀ(2ꢀnitroꢀ1ꢀ
H2N
N
H
phenylethyl)pyrimidinꢀ4(3H)ꢀone (4aa’) was obtained. We
attribute the unexpected result to steric hindrance of istain, which
4
j, 79%
4k, 87%
35 hampers the formation of carbon nitrogen bond (Scheme 2).
4
o, 81%
4
m, 86%
4
4
n, 78%
q, 81%
O
N
NO2
HN
H2N
N
H
Scheme 2 Substrates scope for synthesis of 4.
OMe
4
p, 72%
4r, 80%
The results exhibit the scope and generality of the novel
domino reaction with respect to a range of nitroolefin and
4
0
aldehyde substrates. In view of these results, we turned our
attention to investigate several differently substituted pyrimidine
such as 6ꢀaminopyrimidineꢀ2,4(1H,3H)ꢀdione 5a and 6ꢀaminoꢀ2ꢀ
thioxoꢀ2,3ꢀdihydropyrimidinꢀ4(1H)ꢀone 5b. Unfortunately, as
shown in Scheme 3, the intermediate 6, which could not
participate the subsequent reaction for the formation of
pyrido[2,3ꢀd]pyrimidine 7, was obtained, probably because of the
poor reaction reactive of them.
O
NO2
HN
H2N
N
N
H
4
u, 75%
4
s, 76%
4t, 85%
45
O
NO2
S
HN
H2N
N
N
H
4
v, 84%
4w, 75%
4
x, 86%
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1
00
8
6
4
2
0
0
0
0
0
Yield (%)
1
cycle cycle cycle cycle cycle
st
2nd
3rd
4th
5th
Scheme 3 Scope of different pyrimidine substrates.
Fig. 3 Recyclability of carbonaceous material catalyst.
After accomplishment of the reaction, the crude products
were collected by filtration and were purified by recrystallization
from hot 95% ethanol and N,Nꢀdimethylformamide to afford the
goal products. The structural elucidation was determined by IR,
H and C NMR spectroscopy and HRMS spectra. Additionally,
its relative stereoꢀconfiguration of compound 4a was further
15
On the basis of literature reports and our experiments, a
5
0
5
3
4
4
5
5
5
0
5
0
5
tentative mechanism for the formation of products 4 is outlined in
Scheme 4. The first step involve the Michael addition of
nitroolefin 2, which is activated by CꢀSO H, with 2,6ꢀ
diaminopyrimidinꢀ4(3H)ꢀone 1a to form intermediate A.
Intermediate A undergoes imineꢀenamine tautomerization to give
intermediate B , which further isomerizes to C in the presence of
1
13
3
confirmed by singleꢀcrystal Xꢀray diffraction analysis as shown
14
1
in Fig. 2. The perspective diagram shows that there are three
stereocenters in the molecular structure and the two aryl groups
residing at C5 and C7 positions of the pyrido[2,3ꢀd]pyrimidine
scaffold are in antiꢀconfiguration. All substrates tested afforded
high diastereoselectivity (>99:1) in favor of 5,6ꢀtrans and 6,7ꢀcis
tetrahydropyridopyrimidinone 4. In the experimental procedure,
CꢀSO H. The next step is the condensation reaction involving
3
polarization of carbonyl group by CꢀSO H, followed by
3
nucleophilic attack of the amine group of intermediate B to yield
imine D. Finally, intermediate D undergos an intramolecular
carbonꢀcarbon bond formation to give the nitroꢀMannich product
1
1
we could not found any other isomers by H NMR spectroscopy
4
. As anticipated, the nitroꢀMannich reaction follows the steric
even if the crude product of the model reaction, which exhibited
the excellent diastereoselectivity of the domino reaction.
hindrance rule, providing the product with the two aromatic rings
arranged on the different side, as confirmed by Xꢀray structural
analysis. The regioselectivity is directed by the activities of 2,6ꢀ
diaminopyrimidinꢀ4(3H)ꢀone 1a and aldehydes 3. To test the
proposed mechanism, intermediate C (R1 = 4ꢀOMeC H ) was
isolated separately prepared from 2,6ꢀdiaminopyrimidinꢀ4(3H)ꢀ
one (1a) and (E)ꢀ1ꢀmethoxyꢀ4ꢀ(2ꢀnitrovinyl)benzene (2g) under
the same reaction conditions. Then the reaction of intermediate C
and aldehyde 3a was examined under the above optimal
conditions and the target product 4g was obtained with a yield
similar to that of the threeꢀcomponent oneꢀpot reaction.
Additionally, intermediate C was identified by various spectral
data.
6
4
2
0
Fig. 2. Xꢀray crystal structure of compound 4a.
Subsequently, the reusability of carbonaceous material was
examined by using model reaction of 2,6ꢀdiaminopyrimidinꢀ
4
(3H)ꢀone (1a), (E)ꢀ(2ꢀnitrovinyl)benzene (2a) and 4ꢀ
methylbenzaldehyde (3a). After completion of the reaction, by
cooling the reaction mixture to room temperature, the solid was
filtered, and dissolved in hot ethanol, filtered again and the solid
2
5
o
dried in vacuum oven at 120 C for 4 h, could be reused easily.
The results showed the yields remained almost unchanged even
after the catalyst had been recycled for five times. The slight loss
observed in the catalytic activity after the several runs might be
due to the minor losses in the recovery process (Fig. 3).
3
0
60
Scheme 4 Proposed mechanism for the formation of product 4.
4
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DOI: 10.1039/C7GC03812G
o
DMSOꢀd , 25 C, TMS): δ = 10.13 (br, s, 1H, NH), 7.35ꢀ7.38 (m,
Conclusions
6
6
6
0
5
2H, ArH), 7.26ꢀ7.32 (m, 6H, ArH), 7.24 (s, 1H, NH), 7.15ꢀ7.17
(m, 2H, ArH), 6.24 (br, s, 2H, NH ), 4.97 (t, J = 2.4 Hz, 1H, CH),
4.54 (d, J = 3.6 Hz, 1H, CH), 4.41 (s, d, J = 2.0 Hz, 1H, CH);
NMR (100 MHz, DMSOꢀd , 25 C, TMS): δ = 162.7, 161.8,
60.0, 154.4, 154.0, 142.9, 141.8, 137.4, 129.0, 128.8, 128.7,
128.6, 128.4, 128.2, 127.4, 127.2, 126.8, 89.4, 83.0, 53.0; IR
KBr, ν, cm ): 3385, 2920, 1639, 1550, 1474, 1364, 1328, 1104,
45, 770; HRMS (ESI) m/z calcd for C H N O [M + H] :
19 17 5 3
In summary, we have developed a novel threeꢀcomponent
domino reaction for selective synthesis of pyrido[2,3ꢀ
d]pyrimidine derivatives using carbonaceous material as reusable
catalyst with good yields. The cyclization reaction simultaneously
installs two CꢀC bonds and one CꢀN bond to form three chiral
carbon centers with highly selectivity, showing that the procedure
allows the efficient synthesis of diverse 5,6,7,8ꢀ
2
1
3
C
o
6
1
5
ꢀ1
(
+
8
3
64.1404, found: 364.1410.
tetrahydropyrido[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone
derivatives
1
0
selectively. Advantages of this strategy include easily available
starting materials, the relatively mild conditions, convenient oneꢀ
pot operation, recoverable solid acid catalyst, and excellent regioꢀ,
and diastereoselectivity.
General procedure for the synthesis of 6
In a 10ꢀmL reaction vial, 6ꢀaminopyrimidineꢀ2,4(1H,3H)ꢀdione
7
7
8
8
0
5
0
5
5
a or 6ꢀaminoꢀ2ꢀthioxoꢀ2,3ꢀdihydropyrimidinꢀ4(1H)ꢀone 5b (0.5
mmol), (E)ꢀ1ꢀmethylꢀ4ꢀ(2ꢀnitrovinyl)benzene (0.5 mmol), 4ꢀ
methylbenzaldehyde (0.5 mmol), carbonaceous material (Cꢀ
Experimental section
SO H) (10 mg) as well as water (3.0 mL), were added
3
respectively and then capped. The mixture was stirred until TLC
revealed that conversion of the substrates was complete, then, the
reaction mixture was cooled. The resulted precipitate was filtered
and dried along with the catalyst. The crude product was further
1
5
General
All the reagents were commercially available and used without
further purification, unless otherwise stated. IR spectra were
purified
by recrystallization
from hot
ethanol/N,Nꢀ
1
determined on an FTꢀIRꢀTensor 27 spectrometer. HNMR spectra
dimethylformamide to give the pure desired product. 6ꢀaminoꢀ5ꢀ
(2ꢀnitroꢀ1ꢀ(pꢀtolyl)ethyl)pyrimidineꢀ2,4(1H,3H)ꢀdione (6a), white
were recorded on a 400 MHz instrument (Bruker Avance 400
Spectrometer). Chemical shifts (δ) are given in ppm relative to
TMS as the internal reference, with coupling constants (J) in Hz.
o
1
o
2
2
3
0
5
0
solid, mp: >300 C; H NMR (400 MHz, DMSOꢀd , 25 C,
6
TMS): δ = 10.28 (s, 1H), 10.00 (br, s, 1H, NH), 7.29 (d, J = 8.0
Hz, 2H, ArH), 7.04 (d, J = 8.0 Hz, 2H, ArH), 6.36 (br, s, 2H,
NH ), 5.33ꢀ5.39 (m, 1H, CH ), 5.21ꢀ5.26 (m, 1H, CH ), 4.51 (t, J
13
C NMR spectra were recorded at 100 MHz. Chemical shift
2
2
2
were reported in ppm with the internal chloroform signal at 77.0
ppm or dimethyl sulphoxide signal at 39.9 ppm as a standard.
HRMS (ESI) was measured with a Bruker Daltonics APEXII
instrument. Singleꢀcrystal Xꢀray diffraction measurement was
carried out on a Rigaku Saturn CCD diffractometer at 100(2) K 90 7.05 (d, J = 8.0 Hz, 2H, ArH), 6.59 (br, s, 2H, NH ), 5.35ꢀ5.41 (m,
using graphite monochromated Mο Kα radiation (λ = 0.71073 Å).
=
8.0 Hz, 1H, CH), 2.22 (s, 3H, CH ). 6ꢀaminoꢀ5ꢀ(2ꢀnitroꢀ1ꢀ(pꢀ
3
tolyl)ethyl)ꢀ2ꢀthioxoꢀ2,3ꢀdihydropyrimidinꢀ4(1H)ꢀone
yellow solid, mp: >300 C; H NMR (400 MHz, DMSOꢀd , 25 C,
(6b),
o
o
1
6
TMS): δ = 11.70 (br, s, 2H, NH), 7.28 (d, J = 8.0 Hz, 2H, ArH),
2
1H, CH ), 5.23ꢀ5.28 (m, 1H, CH ), 4.55 (t, J = 7.6 Hz, 1H, CH),
2
2
The structure was solved by direct methods and refined by fullꢀ
2.22 (s, 3H, CH
3
).
2
matrix least squares on F using the SHELXTLꢀ97 program
1
6
package. According to literature method, the solid acid (Cꢀ
Acknowledgements
SO H) catalyst was prepared using furaldehyde and
3
We are grateful for the financial support from the Natural Science
Foundation of Zhejiang Province (No. LY16B020007) and the
financial support from the Education Department of Zhejiang
Province (No. Y201636353). We are also grateful to Wenzhou
University and Beijing Normal University for the help of
structure analysis.
hydroxyethylsulfonic acid as substrates.
9
5
General procedure for the synthesis of 4
3
4
4
5
5
5
0
5
0
5
In a 10ꢀmL reaction vial, 2,6ꢀdiaminopyrimidinꢀ4(3H)ꢀone (0.5
mmol), nitroolefin (0.5 mmol), aldehyde (0.5 mmol),
carbonaceous material (CꢀSO H) (10 mg) as well as water (3.0
3
mL), were added respectively and then capped. The mixture was
stirred until TLC revealed that conversion of the substrates was 100 Notes and references
complete, then, the reaction mixture was cooled. The resulted
1
M. Butters, D. Catterick, A. Craig, A. Curzons, D. Dale, A. Gillmore,
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precipitate was filtered and dried along with the catalyst. The
crude product was further purified by recrystallization from hot
ethanol/N,Nꢀdimethylformamide to give the pure desired product.
2
2
,
,
2
ꢀaminoꢀ6ꢀnitroꢀ5ꢀphenylꢀ7ꢀ(pꢀtolyl)ꢀ5,6,7,8ꢀtetrahydropyrido o
1
05
6
[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone (4a), yellow powder; mp: >300 C;
7
1827ꢀ71851; (c) F. Buron, J. Y. Mérour, M. Akssira, G.
1
o
H NMR (400 MHz, DMSOꢀd , 25 C, TMS): δ = 10.09 (br, s,
6
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1
H, NH), 7.34ꢀ7.38 (m, 2H, ArH), 7.25ꢀ7.29 (m, 3H, ArH), 7.17
(s, 1H, NH), 7.11 (d, J = 8.4 Hz, 2H, ArH), 7.04 (d, J = 8.0 Hz,
2
H, ArH), 6.21 (br, s, 2H, NH ), 4.92 (t, J = 2.6 Hz, 1H, CH), 110
3
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2
4.50 (d, J = 3.2 Hz, 1H, CH), 4.39 (d, J = 2.0 Hz, 1H, CH), 2.27
13
o
(s, 3H, CH3); C NMR (100 MHz, DMSOꢀd , 25 C, TMS): δ =
6
1
61.8, 160.0, 154.4, 143.0, 138.0, 134.3, 130.2, 129.4, 129.0,
28.6, 127.8, 127.4, 127.1, 89.4, 83.0, 52.7, 21.1; IR (KBr, ν, cm
: 3499, 3393, 3064, 2901, 1642, 1594, 1545, 1474, 1385, 1322,
ꢀ
1
1
1
1
15
20
)
1285, 1075, 1030, 770, 621; HRMS (ESI) m/z calcd for
+
C H N O [M + H] : 378.1561, found: 378.1565. 2ꢀaminoꢀ6ꢀ
20
19
5
3
nitroꢀ5,7ꢀdiphenylꢀ5,6,7,8ꢀtetrahydropyrido[2,3ꢀd]pyrimidinꢀ
o
1
4
(3H)ꢀone (4k), brown solid, mp: >300 C; H NMR (400 MHz,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |
5

Green Chemistry
Page 6 of 7
View Article Online
DOI: 10.1039/C7GC03812G
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4
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2
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60
7
8
Crystal data. C22
9.760(3), c = 12.772(4) Å, U = 1047.6(6) Å , T = 100(2) K, space
group Pꢀ1, Z = 2, 1.342 reflections measured, 4847 unique (Rint
H N O , M = 423.47, triclinic, a = 9.324(3), b =
25 5 4
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2
) was
0.1226 (all data).
3
3
0
5
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| Journal Name, [year], [vol], 00–00
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Green Chemistry
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DOI: 10.1039/C7GC03812G
Table of Contents Entry
A highly efficient, operationally simple, green method using solid
acid for regio- and diastereoselective synthesis of
pyrido[2,3-d]pyrimidines