Synthesis of novel fused chromone-pyrimidine hybrids and 2,4,5-trisubstituted pyrimidine derivatives via ANRORC rearrangement

Article abstract of DOI:10.1039/c7nj01839h

A facile and versatile procedure for the synthesis of functionalized novel 2,5-diphenyl-5H-chromeno[4,3-d]pyrimidin-5-ol and (2,4-diphenylpyrimidin-5-yl) (2-hydroxyphenyl) methanone has been described. The key step in the synthesis involves the ANRORC rea

Full text of DOI:10.1039/c7nj01839h

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Synthesis of Novel Fused Chromone-Pyrimidine Hybrids and 2, 4,
5-Trisubstituted Pyrimidine Derivatives via the ANRORC
Rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx
M. Sambaiaha,b , K. Raghavulua, K. Shiva Kumar b, Satyanarayana Yennam a & Manoranjan Behera*a
DOI: 10.1039/x0xx00000x
Abstract: A facile and versatile procedure for the synthesis of functionalized novel 2, 5-diphenyl-5H-chromeno [4, 3-d]
pyrimidin-5-ol and (2, 4-diphenylpyrimidin-5-yl) (2-hydroxyphenyl) methanone has been described. The key step in the
www.rsc.org/
synthesis
involves
the
ANRORC
reaction
of
3-benzoyl
chromones
with
benzamidines
Introduction
Efficient synthesis of polycyclic aromatic hydrocarbons have
attracted much attention due to their diverse biological activities1
as well as electro-chemical and photochemical properties.2 In this
context pyrimidine derivatives are considered highly admired
heterocyclic ring structure.3 Pyrimidine derivatives usually existing
in natural and unnatural products, play the crucial role in human
life.4 Pyrimidine activated sugars are also serve as essential
functions in phospholipid and polysaccharide synthesis,
glucuronidation in detoxification processes, glycosylation of
proteins and lipids.5 In addition, pyrimidines can be salvaged by
human cells for the synthesis of deoxyribonucleotides that are used
for DNA synthesis. Also, pyrimidine derivatives commonly display
remarkable biological and pharmacological activity for human
diseases, such as cancer,6 varicella-zoster virus,7 malaria,8 tumor of
L1210 and P388 leukemias.9 Study indicates that the fusion of
pyrimidine moiety with different heterocycle scaffolds gives rise to
a new class of hybrid heterocycles with improved biological activity
(Fig 1).10
Chemically, chromones (4H-chromene-4-ones) are heterocyclic
compounds with the benzo-γ-pyrone framework. Molecules
containing the chromone or benzopyrone ring have a wide range of
biological activities.11 They have been shown to be tyrosine and
protein kinase inhibitors,12-13 as well as anti-inflammatory,14
antiviral,15 antioxidant16 and antihypertensive agents.15 Chromone
derivatives are also active at benzodiazepine receptors,17 on
lipooxygenase and cyclooxygenase.18 In addition to this, they have
shown to be anticancer agents.19 Chromones may also have
application in cystic fibrosis treatment, as they activate the cystic
fibrosis trans-membrane conductance regulator.20 The vast range of
biological effects associated with this scaffold has resulted the
chromone ring system being considered as a privilege structure.21
O
O
CH3
N
N
O
O
N+
H3C
N
CF3
O-
O
N
(II)
(I)
(III)
OMe
OCH3
O
OH
CH3
N
N
N
N
HO
O
N
H3C
OH
N
N
O
(IV)
(VI)
(V)
Fig 1: Some Biologically active Pyrimidines and Fused Chromone-Pyrimidine Hybrids
Synthesis of hybrid natural products has gained
momentum in recent years.22-24 It is expected that combining
features of more than one biologically active natural segment
in a single molecule may result in pronounced pharmacological
activity while retaining high diversity and biological
relevance.25 Taking into consideration these two biologically
significant structures (Chromone and Pyrimidine), we plan to
develop a general method for the synthesis of chromone-
pyrimidine hybrids and here in we report our initial result.
A major challenge in organic synthesis today is to devise
reactions that can form several C-C and/or C-heteroatom bonds in
one operation leading to the construction of target structures with
proper chemo-, regio and stereo selectivity. In this context domino
(also Known as tandem or cascade) reactions have proven to be a
powerful shortcut for the assembly of complex ring systems
minimizing the waste sub-products and synthetic efforts. During last
three decades domino strategies were successfully applied in the
synthesis of varies practically valuable cyclic compounds including
heterocycles, pharmaceuticals and natural products. Owing to their
special electronic properties the chemistry of heterocyclic systems
like pyrones, chromones and their 3-acyl derivatives, have
experienced a renaissance in recent years, namely they are often
involved in domino transformations since the push-pull fragment in
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pyrone remains labile towards the external and internal domino reaction of 3-benzoyl chromone with benzamidines
nucleophiles.26 (Scheme 2).27 Herein we report an efficient and novel synthesis of
Considering the tendency of chromone framework to undergo functionalized novel 2, 5-diphenyl-5H-chromeno [4, 3-d] pyrimidin-
an ANRORC (Addition of the Nucleophile, Ring Opening and Ring 5-ol and (2, 4-diphenylpyrimidin-5-yl) (2-hydroxyphenyl)
Closure) transformation with various nucleophiles leading to the methanone.
synthesis of numerous valuable systems, we started exploring
compound 7a was confirmed by the NOE, HMBC, HSQC studies, as
there was ambiguity in the structure of compound 7a.31 For the
Results and discussion
confirmation of compound 7a (not 7B in Fig 3) we have performed
15N-NMR studies as it was difficult to differentiate between 7a and
Our synthesis started with the commercially available 2-hydroxy
7B in NOE, HMBC, HSQC studies. Finally 15N-NMR studies confirm
acetophenone 1a (Scheme 1).Thus compound 1a was treated with
the structure of compound 7a (Figure 2).32 The mechanism was
benzoyl chloride 2a in pyridine at room temperature to give the O-
benzoyl protected acetophenone 3a in good yield.28 The compound
proposed for the formation of compound 7a and 8a based on the
literature.31 As proposed by Ghosh et al.31 the reaction proceed
3a was converted to 1, 3-diketone derivative 4a via the Baker
Venkatraman rearrangement using KOH/ pyridine.29 Compound 4a
through a Michael addition at the C-2 position of the chromone
was well characterized by 1H-NMR (keto-enol form) and LC-MS
moiety with concomitant opening of the pyrone ring to form the
analysis. Initially, our aim was to treat compound 4a with DMF-
intermediate 9. The intermediate
9 thus formed undergoes
DMA (N,N-Dimethyformamide dimethyl acetal) to produce
enaminone (Int-1) followed by cyclization to obtain the compound
5a. But the treatment of compound 4a with DMF-DMA/ toluene at
recyclization with subsequent water elimination in two different
pathways to give compound 7a and compound 8a. The pathway (a)
which is energetically favoured, gives the predominant 2, 5-di-aryl-
5-hydroxybenzopyrano-pyrimidine 7a as major product through the
intermediate 10. The pathway (b) leads to minor product 2-aryl-5-
(2-hydroxybenzoyl)-pyrimidine 8a. The intermediate 10 can lose
water molecule in two different modes (path c & path d). The
pathway d relives steric crowding at the benzylic centre and creates
a double bond in conjugation with the benzene ring to give
compound 7a which is energetically more favoured than the other
0
80 C gave the compound 5a directly instead of Int-1. Probably the
intermediate (Int-1) was cyclized in situ in lieu of the hydroxyl group
at the ortho position. This two-step condensation and cyclization
reaction of 1, 3 diketo derivative 4a was reported earlier with low
yield.30 By using this two-step method we have prepared a series of
3-benzoyl chromones (5a-5d in Table1) in very good yields.
Initially we tried the ANRORC reaction of compound 5a with
benzamidine 6a using Et3N as base and THF as solvent at RT. But
even after 12 h we observe most of the SM was unreacted. We
tried several reaction conditions to optimize the ANRORC reaction
of compound 5a with benzamidine 6a and the results are
summarized in Table 2. Finally treatment of compound 5a with
benzamidine 6a in NaOMe/MeOH condition, we could able to
isolate the two compounds by column chromatography. The major
compound was found to be 7a and the minor compound was
assigned the structure as 8a (Figure 2). The structure of the
compounds 7a and 8a were supported by its IR, 1H- NMR, HMBC,
LC-MS and HRMS analysis reports. GHMBC and HSQC experiments
were performed to confirm the structure of compound 8a. In HMBC
experiment (Fig 2), the 7th position OH proton at 11.9 ppm giving
correlation with C-3 at 118.5 ppm, C-4 at 163.1 ppm and C-5 at
119.4 ppm, 10th position carbonyl carbon at 200.6 ppm are giving
correlation with H-6 at 7.25 ppm, H-8 at 8.88 ppm. All protons
versus carbon connectivity’s and 13C chemical shift values are
supporting the structure of compound 8a. The structure of the
pathway
c
that
lead
to
2,
5-di-aryl-10-hydroxy-
dihydrobenzopyrimidine 7B. The formation of pyrimidine ring in the
compound 7a by water elimination of compound 10 in the pathway
d is probably the major reason for exclusive formation of compound
7a not 7B.
To prove the generality of this method various highly
substituted aryl, hetero aryl, alkyl benzamidines as well as poly
substituted 3-benzoyl chromones were examined and the results
were given in Table 3. Similar yields were observed for the
substrates having electron withdrawing groups (compounds 7e, 8e
and 7f, 8f) as well as electron donating groups (compound 7c, 8c; 7j,
8j; 7n, 8n; 7s, 8s and 7t, 8t). More importantly previously
inaccessible furan, pyrimidine and guanidine analogues were
synthesized in very good yield (compound 7r, 8r; 7q, 8q; 7s, 8s and
7t, 8t). Alkyl amidines (acetamidine and guanidine) were also
converted to their fused chromone-pyrimidines as well as tri
substituted pyrimidines in good yield which are not reported in the
literature.
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N
N
HO
Path c
-H2O
..
HN
N
O
7B
NH
OH
O
NH
HO
Path a
O
..
O
10
OH
O
O
O
9
N
N
-H2O
OH
Path d
O
5a
7a
..
ClH.H2N
NH
O
O
-H2O
..
O
N
NH
Path b
6a
N
OH
N
OH
H
8a
9
Fig 3:
Proposed Mechanism for the compounds 7a and 8a
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reaction mixture was evaporated to afford the crude compound
which was purified by silica gel column chromatography (15 %
EtOAc/petroleum ether) to gave the pure compound 5a (5.5 g, 88%)
as white solid. 1H NMR (400 MHz, CDCl3): δ = 8.38 (m, 2H), 7.87 (dd,
2H), 7.76 (t, 1H), 7.57 (m, 2H), 7.48 (m, 3H). MS (EI): m/z 250
(M+1,100).
Conclusions
In summary, we have developed
a facile and versatile
procedure for the synthesis of functionalized novel 2, 5-diphenyl-
5H-chromeno [4, 3-d] pyrimidin-5-ol and (2, 4-diphenylpyrimidin-5-
yl) (2-hydroxyphenyl) methanone. This is the first report of ANRORC
reaction of 3-benzoyl chromone with benzamidines. These findings
will significantly expand the value of chromones in the synthesis of
heterocycles.
2, 4-diphenylpyrimidin-5-yl)(2-hydroxyphenyl)
methanone (8a) & 2, 5-diphenyl-5H-chromeno [4,
3-d] pyrimidin-5-ol (7a): 25 % NaOMe (0.8 ml, 3.6 mmol) in
methanol was taken in methanol under N2 atm, to this compound
6a (0.313 g, 2.00 mmol) was added at RT and stirred for 5 min. Then
compound 5a was added and stirred the reaction mixture at RT for
16 h. The progress of the reaction was monitored by TLC (20% Ethyl
acetate in petroleum ether) showed completion of the reaction.
After completion of the reaction; the reaction mixture evaporated
to afford the crude compound which was purified by silica gel
column chromatography Elution of the column with 10%
EtOAc/petroleum ether to gave the pure compound 7a (0.400 g,
57%) as white solid. M.p. 171-175 °C. 1H NMR (400 MHz, DMSO-d6):
δ = 8.52 (m, 3H), 8.31 (d, 2H), 7.62 (m, 6H), 7.48 (m, 3H), 7.27 (t,
1H), 7.17 (d, 1H). IR (KBr, cm−1): 3469, 3169, 1757, 1598, 1552,
1418, 1048, 957, 753, 692. 13C NMR (100 MHz, CD3COCD3) = 164.8,
156.6, 155.8, 154.5, 142.5, 138.4, 131.7, 131.9, 134.5, 131.9, 129.8,
129.7, 129.5, 129.1, 127.9, 126.2, 125.8, 125.3, 123.2, 121.0, 120.8,
119.1, 99.9. MS (EI): m/z 352 (M+1,100), HRMS: (ESI): Calcd for:
C23H16N2O2 [M+H]: 353.1212; Found: 353.1316.
Elution of the column with 5 % EtOAc/petroleum ether to gave
the pure compound 8a (0.150 g, 21%) as white solid. M.p. 129-133
°C. 1H NMR (400 MHz, CDCl3): δ = 11.90 (s, 1H), 8.87 (s, 1H), 8.64
(m, 2H), 7.76 (dd, 2H), 7.56 (m, 3H), 7.39 (m, 4H), 7.36 (d, 1H), 7.01
(dd, 1H), 6.72 (t, 1H). IR (KBr, cm−1): 3227, 3058, 1971, 1621, 1549,
1419, 1332, 1240, 922, 742, 692. 13C NMR (100 MHz, DMSO-d6) =
196.34, 163.3, 159.3, 156.9, 136.86, 136.80, 136.5, 136.0, 131.4,
130.9, 130.27, 130.2, 129.05, 129.0, 128.8, 128.4, 128.41, 128.14,
128.10, 122.37, 122.3, 119.3, 117.3. MS (EI): m/z 352 (M+1,100),
HRMS: (ESI): Calcd for: C23H16N2O2 [M+H]: 353.1212; Found:
353.1320.
General Experimental Details. Dry solvents were
purchased from chemical suppliers and used without further
purification. Analytical thin-layer chromatography (TLC) was
performed on commercially available Merck TLC Silica gel 60 F254
.
Silica gel column chromatography was performed on silica gel 60
(spherical 100-200 µm). IR spectra were recorded on Perkin-Elmer
FT/IR-4000 using ATR.1H NMR spectra were recorded on Varian-400
(400 MHz) spectrometer. Chemical shifts of 1H NMR spectra were
reported relative to tetra methyl silane. 13C NMR spectra were
recorded on Varian-400 (100 MHz) spectrometer. Chemical shifts of
13C NMR spectra were reported to relative to CDCl3 (77.16) and
DMSO-d6 (39.5). Splitting patterns were reported as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Experimental Procedure for the Preparation of 2-
acetylphenyl benzoate (3a): To a stirred solution of 2-
hydoxy acetophenone (1a) (2 g, 14.68 mmol) in pyridine (3 ml) was
added benzoyl chloride (2a) (2.9 g, 20.56 mmol) at 0 0C and the
reaction mixture was stirred at RT for 1h. The progress of the
reaction was monitored by TLC (5% Ethyl acetate in petroleum
ether) showed completion of the reaction. After completion of the
reaction; the reaction mixture was poured in to ice cold 1N HCl (70
ml) and stirred at RT for 2 h. The solid was filtered and washed with
water and dried under vacuum to give the crude product. The crude
product was washed with n-pentane to afford the pure compound
1
3a (3 g, 85%) as white solid. H NMR (400 MHz, CDCl3): δ = 8.22 (d,
2H), 7.87 (d, 1H), 7.68 (m, 1H), 7.56 (m, 3H), 7.39 (t, 1H), 7.25 (m,
1H), 2.54 (s, 3H). MS (EI): m/z 240 (M+1,100).
1-(2-hydroxyphenyl)-3-phenylpropane-1, 3-dione
(4a): To a stirred solution of compound 3a (2.7g, 11.25mmol) in
pyridine (10 ml) was added NaOH powder (675 mg, 16.87 mmol) at
50 0C and the reaction mixture was stirred at the same temperature
for 1h. The reaction mixture became thick solid. The progress of the
reaction was monitored by TLC (10% Ethyl acetate in petroleum
ether) showed completion of the reaction. After completion of the
reaction; the reaction mixture was acidified with 20 % acetic acid
solution and stirred at RT for 3 h. The yellow coloured solid was
filtered and washed with water and dried under vacuum to afford
the pure compound 4a (2.4 g, 90%) as yellow solid. 1H NMR (400
MHz, CDCl3): δ = 15.54 (s, 1H), 12.09 (s, 1H), 7.93 (m, 2H), 7.78 (dd,
1H), 7.75 (m, 1H), 7.50 (m, 3H), 7.01 (dd, 1H), 6.90 (t, 1H), 6.85 (s,
1H). MS (EI): m/z 240 (M+1,100).
Acknowledgements
Authors are grateful to GVK Biosciences Pvt. Ltd., for the financial
support and encouragement. Help from the analytical department
for the analytical data is appreciated. We thank Dr. Sudhir Kumar
Singh for his invaluable support and motivation.
Notes and references
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DOI: 10.1039/C7NJ01839H
Graphical Abstracts
Synthesis of Novel Fused Chromone-Pyrimidine Hybrids and 2, 4, 5-
Trisubstituted Pyrimidine Derivatives via the ANRORC Rearrangement
M. Sambaiaha,b , K. Raghavulua, K. Shiva Kumar b, Satyanarayana Yennam a & Manoranjan Behera*a
NH
R3
NH2.HCl
R3
OH
N
R3
N
N
O
O
O
R3 =H, Me,2-OMe,3-Cl,4-CF3,4-F,
NH2,3-Py,3-Furan
+
N
R1
OH
O
O
R1
R2
R1
R2
Major
R2
R1= H,3,5-Di Cl,5-Me
R2= H, 3,4,5-OMe
Minor
R1=H, 3,5-Di Cl,5-Me
R2=H, 3,4,5-OMe
R3=H, Me, 2-OMe, 3-Cl, 4-CF3,
4-F,NH2,3-Py,3-Furan
20 Examples