Pot-economic synthesis of diarylpyrazoles and pyrimidines involving Pd-catalyzed cross-coupling of 3-trifloxychromone and triarylbismuth

Article abstract of DOI:10.1007/s12039-018-1565-6

Abstract: The present study reveals the formation of 3,4-diarylpyrazole and 4,5-diarylpyrimidine in one-pot operation starting from 3-trifloxychromone and triarylbismuth. The complete process encompasses two steps in the one-pot operation. The first step leads to the formation of isoflavone via cross-coupling reaction of 3-trifloxychromone and triarylbismuth as a threefold arylating reagent. These isoflavones were further converted into 3,4-diarylpyrazole and 4,5-diarylpyrimidine using hydrazine hydrate and guanidinium chloride in the successive step in the same pot. Interestingly the formation of 3,4-diarylpyrazole was achieved in the shortest reaction time i.e., 30 min that too at room temperature. Overall the developed methodology provides easy access to the medicinally important diarylpyrazole and pyrimidine moiety in one-pot operation and in short reaction time. Graphical Abstract: Synopsis The work presented here describes the novel methodology for the formation of medicinally important heterocycles 3,4-diarylpyrazole and 4,5-diarylpyrimidine in one-pot operation starting from 3-trifloxychromone and triarylbismuth.

Full text of DOI:10.1007/s12039-018-1565-6

J. Chem. Sci.
(2018) 130:165
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-018-1565-6
REGULAR ARTICLE
Pot-economic synthesis of diarylpyrazoles and pyrimidines
involving Pd-catalyzed cross-coupling of 3-trifloxychromone
and triarylbismuth
ABHIJEET KUMARa,b,∗ and MADDALI L N RAOb
aDepartment of Chemistry, School of Physical and Material Sciences, Mahatma Gandhi Central University,
Motihari, Bihar 845 401, India
bDepartment of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh 208 016, India
E-mail: abhijeetkumar@mgcub.ac.in
MS received 9 August 2018; revised 25 September 2018; accepted 2 October 2018
Abstract. The present study reveals the formation of 3,4-diarylpyrazole and 4,5-diarylpyrimidine in one-pot
operation starting from 3-trifloxychromone and triarylbismuth. The complete process encompasses two steps
in the one-pot operation. The first step leads to the formation of isoflavone via cross-coupling reaction of 3-
trifloxychromone and triarylbismuth as a threefold arylating reagent. These isoflavones were further converted
into 3,4-diarylpyrazole and 4,5-diarylpyrimidine using hydrazine hydrate and guanidinium chloride in the
successive step in the same pot. Interestingly the formation of 3,4-diarylpyrazole was achieved in the shortest
reaction time i.e., 30 min that too at room temperature. Overall the developed methodology provides easy access
to the medicinally important diarylpyrazole and pyrimidine moiety in one-pot operation and in short reaction
time.
Keywords. Cross-coupling; triarylbismuth; isoflavones; diarylpyrazoles; diarylpyrimidines; pot-economy.
1. Introduction
anti-cancer activities.4,9 Likewise pyrimidine-based
compounds are known for various biological appli-
cations including as tubulin polymerization inhibitors
(Figure 1d).10,11 Phenol-substituted pyrazoles can eas-
ily be converted to phenanthropyrazoles.12 Apart from
that, pyrazole derivatives are also known to serve as
insecticides,13 fungicides14 and as versatile ligands.15,16
There have been a few synthetic methods for the
preparation of aryl substituted pyrazoles17–23 and pyrim-
idines.10,24,25 Among those, the phenol substituted pyra-
zoles and pyrimidines have been obtained using
isoflavones as a precursor. The vast therapeutic value
associated with these phenol substituted 3,4-diarylpyra-
zoles and 4,5-diaryl-2-aminopyrimidines prompted us
to develop a pot-economic protocol for their synthesis
involving in situ formation of isoflavones using triaryl-
Pyrazoles and pyrimidines are significant scaffolds
present in several biologically active molecules as well
as in drug molecules.1–10 These are known to exhibit a
vast range of biological activities such as anti-tumour,3,4
anti-inflammatory,5 anti-depressant6 and so on. In par-
ticular, diaryl pyrazoles and pyrimidines are present as
core moieties in a number of drugs and agrochemicals.
Figure 1 shows example of few drugs with arylated pyra-
zole or pyrimidines as core scaffold which are being
prescribed to treat various physiological disorders. For
example, Celecoxib (Figure 1a),7 is an example of
non-steroidal anti-inflammatory drug (NSAID) and is
known to be COX-2 (cyclooxygenase-2) inhibitors.1
Rosuvastatin(Figure1b)isadrugforcardiovasculardis-
orders.8 Importantly, phenol substituted pyrazoles and
pyrimidines have exhibited appealing biological prop-
erties. For example, 3,4-diarylpyrazole (Figure 1c) has
been studied as heat shock protein inhibitors and with
bismuths
under
Pd-catalyzed
condition.26
Utilization of triarylbismuths with sub-stoichiometric
loadings in cross-coupling reactions is practically use-
ful in organic synthesis.27–33 It was envisaged that
the isoflavones obtained from cross-coupling reaction
using triarylbismuth could further be converted to
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-018-1565-6) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

165 Page 2 of 11
J. Chem. Sci.
(2018) 130:165
3,4-diarylpyrazoles and pyrimidines in one-pot
operation. For the cross-coupling step, it was decided
to employ 3-trifloxychromone as electrophilic coupling
partner as the reactivity of this substrate has not been
investigated so far in couplings with triarylbismuth
reagents. Overall, our aim was to develop efficient
pot-economic methods for the synthesis of phenol-
substituted diarylpyrazoles and pyrimidines by clubbing
cross-coupling step for the formation of isoflavone
as well as their transformation to diarylpyrazoles and
pyrimidines.
was allowed to stir at rt for 18 h. After complete con-
sumption of starting materials, acetic acid (30% v/v) was
added to neutralize the reaction mixture. The precipitate
obtained was filtered and washed with water. It was fur-
ther purified through crystallization from ethanol to obtain
compound 1A as yellow solid in 80% yield (7.4 g).
Step 2: Preparation of 3-hydroxy-2-(4-methoxyphenyl)-
4H-chromen-4-one (2A): To an oven dried round bottom
flask, compound 1A (5.0 g, 19.6 mmol) was taken in
ethanol. To this, sodium hydroxide (1.5 g, 39.3 mmol) was
added at ice-bath temperature. The mixture was stirred
for 10 min and was added H2O2 (30% w/v, 5.0 mL,
43.2 mmol). It was allowed to stir at rt for 18 h. It was
acidified with dil HCl and the yellow precipitate obtained
was filtered and dried under vacuum. It was further puri-
fied by crystallization in ethanol to obtain 2A in 73% yield
(3.8 g).
2. Experimental
2.1 General
For structural characterization, NMR spectra were recorded
on JEOL-400 MHz (JNM ECS-400) spectrometer. WATERS-
Q-Tof Premier-HAB213, in addition to WATERS GCT
Premier-CAB155 instrument, were used for HRMS measure-
ments. The Bruker Vector 22 FTIR spectrometer was used in
IR measurements. Standard drying methods were followed
for the distillation of solvents prior to use. All the coupling
reactions were performed using oven-dried Schlenk tubes
under inert atmosphere conditions. The 3-trifloxychromones
(1a–1e) required for coupling reactions were obtained fol-
lowing the literature procedures.34–36a The triarylbismuth
compounds were prepared by adopting the known proce-
dures.36b−c All the products were isolated using column
chromatography with silica gel (100–200 mesh) and GF-254
silica gel (Merck) for thin layer chromatography.
(B) Representative procedures for the preparation of
3-hydroxychromones:35
Step1:Preparationof(E)-3-(dimethylamino)-1-(2-hydro-
xyphenyl)prop-2-en-1-one (1B): To an oven dried round
bottom flask, 2-hydroxyacetophenone (10.0 mL,
83.0mmol)and N,N-dimethylformamidedimethylacetal
(10.0 mL, 83.0 mmol) were charged. It was refluxed for
1 h. The reaction mixture was cooled to rt. The red precip-
itate was filtered and washed with petroleum ether to get
enamide, (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)
prop-2-en-1-one in 94% yield (19.8 g). It was used in
the next step without further purification.
Step 2: Preparation of 4H-chromen-4-one (2B): To an
oven dried round bottom flask, (E)-3-(dimethylamino)-1-
(2-hydroxyphenyl)prop-2-en-1-one (10.0 g, 53.0 mmol)
was dissolved in dichloromethane (50.0 mL). To this,
conc. HCl (50 mL) was added and the mixture was
refluxed for 1 h. It was cooled to rt and poured into cold
water. The organic layer was separated and the aqueous
layer was extracted with dichloromethane (2 × 30 mL).
The combined organic extract was washed with water
and brine and dried over anhydrous MgSO4. The solvent
was evaporated and dried under vacuum to obtain 4H-
chromen-4-one as red solid in 90% yield (6.8 g).
2.2 Representative procedures for the preparation of
3-trifloxychromones (Scheme 1)
(A) Representative procedure for the preparation of 2-aryl-3-
hydroxyflavones:34
Step 1: Preparation of (E)-1-(2-hydroxyphenyl)-3-(4-
methoxyphenyl)prop-2-en-1-one (1A): To an oven dried
round bottom flask, 2ꢀ-hydroxyacetophenone (5.0 g,
36.72 mmol) and p-anisaldehyde (4.5 mL, 36.72 mmol)
were charged in ethanol. To this, sodium hydroxide (6.3 g,
157.8 mmol) was added at 0 ◦C and the reaction mixture
Step 3: Preparation of 3-hydroxychromone (3B): To an
oven dried round bottom flask 4H-chromen-4-one (5.0 g,
(a)
(b)
(c)
(d)
Figure 1. Pyrazole and pyrimidine-based biological scaffolds and drugs.

J. Chem. Sci.
(2018) 130:165
Page 3 of 11 165
Scheme 1. Synthesis of functionalized 3-trifloxychromones.
34.2 mmol) was dissolved in dichloromethane (50 mL). 2.3 Representative procedure for cross-coupling
Sodium hydroxide (2.0 g, 51.3 mmol) was added to it.
reaction
Reaction mixture was cooled to 0 ◦C and H2O2 (30%
w/v, 13.5 mL, 119.7 mmol) was slowly added at the Representative cross-coupling procedure for Tables 1 and 2:
same temperature. After complete addition, the mixture A hot-oven dried Schlenk tube was charged with 1a
was stirred at 0–15◦C. After complete disappearance of (0.164 g, 0.412 mmol), tri(p-anisyl)Bi (0.066 g,
chromone as monitored by TLC, it was quenched with 0.125 mmol), Pd(PPh3)4 (0.012 g, 0.011 mmol), K3PO4
water and extracted with dichloromethane (3 × 20 mL). (0.053 g, 0.25 mmol), and DMF (3 mL) under N2 atmosphere.
The combined organic extract was washed with water The reaction mixture was stirred in an oil bath at 90 ◦C for 4 h.
and brine, dried over anhydrous MgSO4 and evaporated At the end of the reaction time, the contents were brought to rt,
using rotatory evaporator. In the second step, conc. HCl quenched with water (10 mL) and extracted with ethyl acetate.
(50 mL) was added to the crude reaction mixture and was Theorganicextractwastreatedwithbrine, driedusingMgSO4
stirred at 70 ◦C for 1 h. After that, it was cooled to rt and and was concentrated under reduced pressure. The crude
poured into water. The solid precipitate obtained was fil- product was subjected to silica gel column chromatography
tered and washed with water and dried under vacuum to using 10% EtOAc/petroleum ether as eluent to obtain product
obtain a white solid as 3-hydroxychromone in 64% yield 2.1 as white solid (0.109 g, 81%). For the yield calculation,
(3.54 g).
0.375 mmol of the product was considered as 100% yield.
(C) Representative procedure for the preparation of triflate
derivatives:36
2.4 Pot-economic synthesis of
To a two-neck round bottom flask 3-hydroxychromone
(5.0 g, 18.5 mmol) was charged in dry dichloromethane
2-(4-phenyl-1H-pyrazol-3-yl)phenol (3.1, Table 3)
(50 mL). The mixture was cooled to 0 ◦C and triethy- A hot-oven dried Schlenk tube was charged with 1c
lamine (3.0 mL, 22.2 mmol) was added with continuous (0.121 g, 0.412 mmol), BiPh3 (0.055 g, 0.125 mmol),
stirring for 10 min followed by triflic anhydride (4.6 mL, Pd(PPh3)4 (0.012 g, 0.011 mmol), K3PO4 (0.053 g, 0.25 mm
27.7 mmol) and the resultant mixture was allowed to stir at rt ol), and DMF (3 mL) under N2 atmosphere. The reaction mix-
for 10 h. After that, it was quenched with water and extracted ture was stirred in an oil bath at 90 ◦C for 4 h. At the end of the
with dichloromethane (3 × 20 mL) and dried over anhydrous reaction time, the contents were brought to rt and hydrazine
MgSO4 and concentrated. It was purified by silica gel column hydrate (0.03 mL, 0.625 mmol) was added to the reaction
chromatography (5% EtOAc/petroleum ether) to obtain 1c as mixture. It was further stirred at rt for 30 min. After it was
white solid (3.9 g, 72%).
quenched with water (10 mL) and extracted with ethyl acetate.

165 Page 4 of 11
J. Chem. Sci.
(2018) 130:165
Table 1. Screening for 3-trifloxychromone coupling.a−e
Entry
Catalyst
Base (equiv.)
Temp. (oC)
Solvent
Yield 2.1 (%)
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
None
K3PO4 (6)
K3PO4 (1)
K3PO4 (2)
K3PO4 (3)
K3PO4 (2)
K3PO4 (2)
Cs2CO3 (2)
K2CO3 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
None
90
90
90
90
90
90
90
90
60
100
90
90
90
90
90
DME
DMF
DMF
DMF
DMA
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
46
58
81
76
77
65
54
60
9
48
10
11
12
13
14
15
77
72c
80d
52e
30
K3PO4 (2)
None
aReaction conditions: 1a (0.412 mmol, 3.3 equiv.), Bi(p-anisyl)3 (0.125 mmol, 1 equiv.) Pd(PPh3)4 (0.011 mmol, 0.09 equiv.)
K3PO4 (0.25 mmol, 2 equiv.), DMF (3 mL), 4 h, 90 ◦C. bIsolated yields based on three aryl couplings from BiAr3 reagents
cWith 3 h. dWith 5 h. eWith 0.05 equiv. catalyst.
Theorganicextractwastreatedwithbrine, driedusingMgSO4 in good yields following method A and B as given
in Scheme 1.34–36 Next, the cross-coupling reactiv-
and the solvent was concentrated under reduced pressure. The
crude product was subjected to silica gel column chromatog-
ity of 3-trifloxychromones with triarylbismuth reagent
raphy using 15% EtOAc/petroleum ether as eluent to obtain
3.1 as white solid (0.067 g, 76%).
was explored. It was investigated to establish an opti-
mized protocol under Pd-catalyzed conditions (Table 1).
It was done initially using 2-(p-methoxyphenyl)-3-
2.5 Pot-economic synthesis of
2-(2-amino-5-phenylpyrimidin-4-yl)phenol (4.1,
Table 5)
trifloxychromone (1a) and tri(p-anisyl)bismuth using
catalytic PdCl2(PPh3)2 conditions and K3PO4 base in
DME at 90 ◦C (entry 1, Table 1).26 This catalytic proto-
col furnished the desired isoflavone 2.1 in 46% yield
(entry 1, Table 1). Another attempt using catalytic
Pd(PPh3)4 afforded 2.1 in 58% yield (entry 2, Table 1).
However, it was dramatically improved to 81% yield
when the reaction was performed with 2 equiv. of base
(entry 3, Table 1). Further improvement was not seen
with 3 equiv. of the base (entry 4, Table 1). At this
stage, more investigations were carried out in different
solvents using N,N-dimethylacetamide (DMA) and N-
methyl-2-pyrrolidone (NMP).
In these cases, we did not witness any further
improvement in the cross-coupling yield (entries 5 and
6, Table 1). The impact of Cs2CO3 and K2CO3 base con-
dition proved to be ineffective (entries 7 and 8, Table 1).
The cross-couplings performed at 60 and 100 ◦C condi-
tions found to be low yielding (entries 9 and 10, Table 1).
Additional check with different time durations proved to
The cross-coupling reaction with 1c was carried according
to the procedure given in 2.3. After that, guanidinium chlo-
ride (0.048 g, 0.5 mmol) and NaOH (0.050 g, 1.25 mmol)
were added to the reaction mixture. It was further stirred at
90 ◦C for 10 h. The product mixture was quenched with water
(10 mL) and neutralized with dil. HCl. It was further extracted
with ethyl acetate. The organic extract was treated with brine,
dried using MgSO4 and concentrated under reduced pressure.
The crude product was subjected to silica gel column chro-
matography using 10% EtOAc/dichloromethane as eluent to
obtain product 4.1 as yellow solid (0.078 g, 79%).
3. Results and Discussion
Therequired3-trifloxychromones(1a–1e)forthisinves-
tigation were accessed through literature procedures

J. Chem. Sci.
(2018) 130:165
Page 5 of 11 165
Table 2. Cross-couplings of functionalized 3-trifloxychromones.a−c
Entry 3-Trifloxychromone
Product
Yield (%)
81
1
1a
2.1
2.2
2.3
2
65
68
67
1a
3
1b
4
1b
2.4
5
78
1b
2.5
2.6
6
75
79
77
82
79
1c
7
2.7
2.8
1c
8
1c
9
2.9
1c
10
2.10
1c
11
65
1c
2.11
12
71
75
82
1c
2.12
2.13
2.14
13
1d
14
1d
15
82
73
62
1d
2.15
2.16
16
1d
17
2.17
2.18
2.19
1e
18
64
64
1e
19
1e
aReaction conditions: 3-Trifloxychromone, 1a–1e (0.412 mmol, 3.3 equiv.) BiAr3 (0.125 mmol, 1 equiv.) Pd(PPh3)4
(0.011 mmol, 0.09 equiv.) K3PO4 (0.25 mmol, 2 equiv.) DMF (3 mL), 90 ◦C, 4 h. bIsolated yields based on threefold coupling
from triarylbismuth reagents and 0.375 mmol corresponds to a 100% yield. cHomo-coupled biaryls formed 10–15% amounts.

165 Page 6 of 11
J. Chem. Sci.
(2018) 130:165
Table 3. Pot-economic synthesis of 3,4-diaryl-1H-pyrazoles.a−c
Entry 3-Trifloxychromone
3,4-Diarylpyrazole
Yield (%)
76
1
1c
3.1
2
72
80
1c
3.2
3.3
3
1c
4
67
1c
3.4
5
71
74
60
1c
3.5
3.6
6
1c
7
1c
3.7
8
78
78
74
66
75
1c
3.8
3.9
9
1c
10
1c
3.10
3.11
11
1c
12
1d
3.12
3.13
3.14
13
55
62
1d
14
1e
aReaction conditions: for step 1: 3-Trifloxychromone, 1c–1e (0.412 mmol, 3.3 equiv.) BiAr3 (0.125 mmol, 1 equiv.) Pd(PPh3)4
(0.011 mmol, 0.09 equiv.) K3PO4 (0.25 mmol, 2 equiv.) DMF (3 mL), 90 ◦C, 4 h for Step 2: hydrazine hydrate (0.625 mmol,
5 equiv.) rt, 0.5 h. bIsolated yields based on threefold coupling from triarylbismuth reagents and 0.375 mmol of 3.4-
diarylpyrazole corresponds to a 100% yield. cHomo-coupled biaryls formed 10–15% amounts.

J. Chem. Sci.
(2018) 130:165
Page 7 of 11 165
Table 4. Screening for pyrimidine formation.a−b
Entry
Temp. (oC)
Time (h)
Yield (%)
1
2
3
4
rt
34
13
10
7
74
77
79
56
70
90
90
Figure 2. X-ray structural analysis for 3.10
aReaction conditions: for Step 1, 1c (0.412 mmol, 3.3 equiv.),
BiAr3 (0.125 mmol, 1 equiv.), Pd(PPh3)4 (0.011 mmol,
0.09 equiv.), K3PO4 (0.25 mmol, 2 equiv.), DMF (3 mL),
90 ◦C, 4 h for Step 2, guanidinium chloride (0.5 mmol,
4equiv.), NaOH(1.25mmol, 10equiv.), temp., time. bIsolated
yields.
(CCDC No. 1412753).39
be less effective (entries 11 and 12, Table 1). To optimize
the catalyst loading, a coupling reaction was performed
with 0.05 equiv. of catalyst and this gave 52% yield
(entry 13, Table 1). The absence of either base or cata- cross-coupling process.22,23 This search also revealed
lyst proved to be ineffective as they were crucial for an that not many pot-economic protocols were readily
effective coupling process (entries 14 and 15, Table 1). available with a possibility to combine two or more reac-
With this study, it was realized that the protocol tions in a one-pot operation. Further, the known protocol
involving Pd(PPh3)4 (0.09 equiv.) and K3PO4 (2 equiv.) in this regard requires longer reaction time for access
in DMF at 90 ◦C for 4 h as promising for the effective 3,4-diarylpyrazoles in a one-pot operation and this
cross-coupling of 3-trifloxychromone with triarylbis- encouraged us to further explore any further improve-
muth reagent (entry 3, Table 1). With this optimized ment. Hence additional efforts were made with a view to
protocol, the cross-coupling reactivity of various func- developing a pot-economic combined protocol for the
tionalized 3-trifloxychromones was further investigated synthesisof3,4-diarylpyrazolesusingourrapidprotocol
(Table 2). The coupling reaction of 1a was first evalu- conditions. To start with, it was done with the addition of
atedagainstdifferenttriarylbismuthreagents. Thisstudy hydrazine hydrate to the reaction mixture obtained after
delivered a facile cross-coupling performance with the the cross-coupling step. Quantitative formation of 3,4-
formation of differently functionalized isoflavones in diarylpyrazole was observed at rt in just 0.5 h conditions.
good to high yields (entries 1–19, Table 2). Further,
As reported, this transformation with an organoboron
this also revealed the possibility for chemo-selective reagent such as arylboronic acid under the Suzuki cou-
couplings when the reactive bromo group in 1b and pling conditions requires longer reaction time.22 Hence
1e got survived during the coupling course under the it was of interest to further expand the scope for the
optimized conditions (entries 3–5 and 17–19, Table 2). development of a viable method for rapid access of
Other studies with electronically variant triphenylbis- pyrazoles in a one-pot operation. This resulted in the
muth reagents also demonstrated viable reactivity under preparation of a library of 3,4-diarylpyrazoles and these
our optimized conditions (entries 6–12, Table 2). Even results are as given in Table 3. This pot-economic
the vinyl group was intact when coupling was performed protocol involving cross-couplings with triarylbismuths
with vinyl substituted triphenylbismuth reagent (entry followed by reaction with hydrazine afforded a variety
6, Table 2). This amply reflected the overall efficacy of of 3,4-diarylpyrazoles in a facile manner.
the established palladium protocol conditions to deliver
In general, the fast formation of 3,4-diarylpyrazoles
a library of isoflavones in high yields. Encouraged by was achieved when differently functionalized isoflavo-
this, it was further decided to explore a pot-economic nes were smoothly transformed under our pot-economic
protocol by combining the cross-coupled synthesis of protocol conditions. We also obtained single crystal X-
isoflavones and their in situ conversion to either 3,4- ray analysis of 3.10 (Figure 2) and this unequivocally
diarylpyrazoles or 4,5-diarylpyrimidines. For example, established the formation of 3,4-diarylpyrazole.
a brief literature search revealed that such transforma-
It further encouraged us to establish a pot-economic
tion of isoflavone to pyrazole was performed with the protocol for the synthesis of various 4,5-diarylpyrimi-
direct reaction of isoflavones with hydrazine or after the dines. It was done through the initial generation of

165 Page 8 of 11
J. Chem. Sci.
(2018) 130:165
Table 5. Pot-economic synthesis of 4,5-diaryl 2-amino-pyrimidines.a−c
Entry 3-Trifloxychromone
4,5-diaryl 2-aminopyrimdines
Yield (%)
79
1
1c
4.1
2
74
68
1c
4.2
4.3
3
1c
4
79
61
68
72
1c
4.4
4.5
5
1c
6
1c
4.6
4.7
7
1c
aReaction conditions: for step 1, 1c (0.412 mmol, 3.3 equiv.), BiAr3 (0.125 mmol, 1 equiv.), Pd(PPh3)4 (0.011 mmol,
0.09 equiv.), K3PO4 (0.25 mmol, 2 equiv.), DMF (3 mL), 90 ◦C, 4 h For step 2, guanidinium chloride (0.5 mmol, 4 equiv.),
b
NaOH (1.25 mmol, 10 equiv.), 90 ◦C, 10 h. Isolated yields based on threefold coupling from triarylbismuth reagents and
0.375 mmol of pyrimidine corresponds to a 100% yield. cHomo-coupled biaryls formed 10–15% amounts.
isoflavone followed by its reaction with guanidinium
chloride in a one-pot operation. A trial reaction was ini-
tially carried out with guanidinium chloride after the
cross-coupling step at room temperature. It delivered
74% of 4,5-diaryl-pyrimidine (4.1) in 34 h reaction
time (entry 1, Table 4). In order to reduce the reaction
time, thereactionconditionwasinvestigatedbyoptimiz-
ing the reaction temperature (entries 2 and 3, Table 4).
At 90 ◦C, quantitative conversion of isoflavone to 4,5-
diarylpyridimine was achieved in 10 h (entry 3, Table 4).
On decreasing the reaction time at the same tempera-
ture, the yield of 4,5-diarylpyrimidine decreased to 56%
(entry 4, Table 4).
Figure 3. X-ray structural analysis of 4.4
(CCDC No. 1412754).39
Reaction attempted without the addition of base in
the second step did not provide desired 4,5-diaryl-
pyrimidine (4.1). Hence further study for the conversion
of isoflavone to 4,5-diarylpyrimidine was continued
with 90 ◦C and 10 h condition in presence of an addi-
tional base in a second step. This optimized reaction

J. Chem. Sci.
(2018) 130:165
Page 9 of 11 165
Figure 4. Proposed mechanism for the formation of diarylpyrazole and pyrimidine.
condition was applied in the synthesis of various formation of isoflavones (A) through Pd-catalyzed
functionalized 4,5-diarylpyrimidines (Table 5). The cross-coupling reaction.26
cross-coupling of 1c was carried out with different
In the second step, it was expected to undergo cyclo-
triarylbismuth reagents followed by the reaction of condensation with hydrazine involving nucleophilic
guanidinium chloride. This pot-economic protocol thus attack of hydrazine (B), ring opening (C) followed
gave 4,5-diarylpyrimidines (4.1–4.7) in good to high by cyclocondensation to give 3,4-diarylpyrazole (D).12
yields. It is notable that this pot-economic protocol for Whereas the formation of 4,5-diarylpyrimidines is
the preparation of 4,5-diarylpyrimidines is synthetically expected to begin with the base-mediated ring opening
more viable as it involves triarylbismuth reagents in sub- of isoflavone37,38 leading to F which undergoes conden-
stoichiometric loading with faster reactivity and overall sation with guanidine to give 4,5- diarylpyrimidine (G).
high yields. Our efforts thus unequivocally established
the compatibility of triarylbismuth cross-coupling con-
ditions in further developing pot-economic combined
protocols for rapid access of 3,4-diarylpyrazoles and
4,5-diarylpyrimidines in high yields.
4. Conclusions
We have disclosed an efficient method for the synthesis
of 3,4-diarylpyrazoles and 4,5-diarylpyrimidines start-
ing with triarylbismuth as threefold arylating reagent
and 3-trifloxychromones. These pot-economic proto-
cols provide the rapid access to medicinally impor-
tant 3,4-diarylpyrazoles and 4,5-diarylpyrimidines in
high yields. It is important to highlight that 3,4-
diarylpyrazolescanbeobtainedatroomtemperatureand
within 30 min reaction time, the shortest time reported
so far.
Further, the crystal structure obtained for 2-(2-amino-
5-arylpyrimidin-4-yl) phenol (4.4) is given in Figure 3.
Overall, an easy accessibility of isoflavones through
cross-couplings under catalytic palladium conditions
and their subsequent cyclocondensation to give 3,4-
diarylpyrazoles under pot-economic protocol condi-
tions is expected to have a definitive advantage in
organic synthesis.24 And this advantage also applies to
thetransformationofisoflavoneswithguanidinetorapid
access to 4,5-diarylpyrimidines under pot-economic
protocol conditions.
Supplementary Information (SI)
Characterization data and spectra (1H, 13C NMR, Mass) of
the compounds included in Tables 2, 3, 5 are given in the
supplementary information which is available at www.ias.ac.
3.1 Mechanism
As shown in Figure 4, the formation of 3,4-diarylpyra-
zoles and 4,5-diarylpyrimidines involves the initial in/chemsci.

165 Page 10 of 11
J. Chem. Sci.
(2018) 130:165
Acknowledgements
from isoflavones by two dehydration processes Green
Chem. 15 1048
We acknowledge the financial support (No. 02(0091)/12/
EMR-II) received from the Council of Scientific and Indus-
trial Research (CSIR), New Delhi for this work. A.K. sin-
cerely acknowledges the support of Scientific and Industrial
Research (CSIR), New Delhi for fellowships and also thanks
IIT Kanpur for providing financial assistance and infrastruc-
ture. He sincerely acknowledges the support for Mahatma
Gandhi Central University for providing all other support.
13. Jiang D, Zheng X, Shao G, Ling Z and Xu H 2014 Dis-
covery of a novel series of phenyl pyrazole inner salts
based on fipronil as potential dual-target insecticides J.
Agric. Food Chem. 62 3577
14. Wu Z, Hu D, Kuang J, Cai H, Wu S and Xue W 2012
Synthesis and antifungal activity of N-(substituted
pyridinyl)-1-methyl(phenyl)-3-(trifluoromethyl)-1H-
pyrazole-4 carboxamide derivatives Molecules 17
14205
15. Mukherjee R 2000 Coordination chemistry with
pyrazole-based chelating ligands: molecular structural
aspects Coord. Chem. Rev. 203 151
16. Ward M D, McCleverty J A and Jeffery J C 2001 Coor-
dination and supramolecular chemistry of multinucleat-
ing ligands containing two or more pyrazolyl-pyridine
‘arms’ Coord. Chem. Rev. 222 251
References
1. Kucukguzel Guniz S and Senkardes S 2015 Recent
advances in bioactive pyrazoles Eur. J. Med. Chem. 97
786
17. Vanjari R, Guntreddi T, Kumar S and Singh K N
2015 Sulphur promoted C(sp3)−C(sp2) cross dehydro-
genative cyclisation of acetophenone hydrazones with
aldehydes: efficient synthesis of 3,4,5-trisubstituted 1H-
pyrazoles Chem. Commun. 51 366
18. Perez-Aguilar M C and Valdes C 2013 Regioselec-
tive one-step synthesis of pyrazoles from alkynes and
N-tosylhydrazones: [3+2] dipolar cycloaddition/[1,5]
sigmatropic rearrangement cascade Angew. Chem. Int.
Ed. 52 7219
19. Tasch B O A, Bensch L, Antovic D and Müller T J J 2013
Masuda borylation–Suzuki coupling (MBSC) sequence
of vinylhalides and its application in a one-pot synthesis
of 3,4-biarylpyrazoles Org. Biomol. Chem. 11 6113
20. Hao L, Hong J-J, Zhu J and Zhan Z-P 2013 One-pot syn-
thesis of pyrazoles through a four-step cascade sequence
Chem. Eur. J. 19 5715
2. Lagoja I M 2005 Pyrimidine as constituent of natural
biologically active compounds Chem. Biodivers. 2 1
3. Daidone G, Maggio B, Plescia S, Raffa D, Musiu C,
Milia C, Perra G and Marongiu M E 1998 Antimicro-
bial and antineoplastic activities of new 4-diazopyrazole
derivatives Eur. J. Med. Chem. 33 375
4. Zaninetti R, Cortese S V, Aprile S, Massarotti A, Canon-
ico P L, Sorba G, Grosa G, Genazzani A A and Pirali T
2013 A concise synthesis of pyrazole analogues of com-
bretastatin A1 as potent anti-tubulin agents ChemMed-
Chem 8 633
5. Badawey E-S A M and El-Ashmawey I M 1998 Nons-
teroidal antiinflammatory agents—part 1: antiinflamma-
tory, analgesic and antipyretic activity of some new 1-
(pyrimidin-2-yl)-3-pyrazolin-5-ones and 2-(pyrimidin-
2-yl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-ones Eur. J.
Med. Chem. 33 349
21. Heller S T and Natarajan S R 2006 1,3-Diketones from
acid chlorides and ketones: a rapid and general one-pot
synthesis of pyrazoles Org. Lett. 8 2675
22. Xie F, Cheng G and Hu Y 2006 Three-component,
one-pot reaction for the combinatorial synthesis of 1,3,4-
substituted pyrazoles J. Comb. Chem. 8 286
23. Zhang Z-T, Tan D-J and Xue D 2007 A concise one-
pot synthesis of 3,4-diaryl-1H-pyrazoles from natural
isoflavones and hydrazine hydrate Helv. Chim. Acta 90
2096
6. Abdel-AzizM, Abuo-Rahma GEl-dinAandHassanAA
2009 Synthesis of novel pyrazole derivatives and evalua-
tion of their antidepressant and anticonvulsant activities
Eur. J. Med. Chem. 44 3480
7. Datar P A and Jadhav S R 2014 Development of pyrazole
compounds as antidiabetic agent: a review Lett. Drug
Design Discov. 11 686
8. Tartaggia S, Ferrari C, Pontini M and Luchhi O D 2015 A
practical synthesis of rosuvastatin and other statin inter-
mediates Eur. J. Org. Chem. 2015 4102
24. Zhang Z-T, Xu F-F, Gao M-X and Qiu L 2009 One-
pot synthesis of 4,5-biphenyl-2-pyrimidinylguanidine
derivatives J. Comb. Chem. 11 880
25. Frasinyuk M S, Bondarenko S P and Khilya V P
2006 Reaction of analogs of natural isoflavonoids with
amidines Chem. Nat. Comp. 42 673
26. Rao M L N, Venkatesh V and Jadhav D N 2009 Pd-
catalyzed efficient cross-couplings of 3-iodochromones
with triaryl-bismuths as substoichiometric multicou-
pling organometallic nucleophiles Synlett 16 2597
27. Dawood K M 2007 Microwave-assisted Suzuki–
Miyaura and Heck–Mizoroki cross-coupling reactions
of aryl chlorides and bromides in water using stable
benzothiazole-based palladium(II) precatalysts Tetrahe-
dron 63 9642
9. Cheung K-M J, Matthews T P, James K, Rowlands M G,
Katherine J, Boxall K J, Sharp S Y, Maloney A, Roe S M,
Prodromou C, Pearl L H, Aherne G W, McDonald E and
Workman P 2005 The identification, synthesis, protein
crystal structure and in vitro biochemical evaluation of a
new 3,4-diarylpyrazole class of Hsp90 inhibitors Bioorg.
Med. Chem. Lett. 15 3338
10. Xie F, Zhao H, Li D, Chen H, Quan H, Shi X, Lou L
and Hu Y 2011 Synthesis and biological evaluation of
2,4,5-substituted pyrimidines as a new class of tubulin
polymerization inhibitors J. Med. Chem. 54 3200
11. Xie F, Zhao H, Zhao L, Lou L and Hu Y 2009 Synthe-
sis and biological evaluation of novel 2,4,5-substituted
pyrimidine derivatives for anticancer activity Bioorg.
Med. Chem. Lett. 19 275
28. Felpin F-X 2005 Practical and efficient Suzuki-Miyaura
cross-coupling of 2-iodocycloenones with arylboronic
12. Wang Q, Zhang Z, Du Z, Hua H and Chen S 2013
One-pot synthesis of 2H-phenanthro[9,10-c]pyrazoles

J. Chem. Sci.
(2018) 130:165
Page 11 of 11 165
II
η6
acids catalyzed by recyclable Pd(0)/C J. Org. Chem. 70
8575
29. Akrawi O A, Patonay T, Konya K and Langer P
relationships of targeted Ru ( -p-cymene) anticancer
complexes with flavonol-derived ligands J. Med. Chem.
55 10512
2013 Chemoselective Suzuki-Miyaura cross-coupling 35. Spadafora M, Postupalenko V Y, Shvadchak V V, Klym-
reactions of 6-bromo-3- (trifluoromethylsulfonyloxy)
flavones Synlett 24 0860
30. Zhang Z, Qiao J, Wang D, Han L and Ding R 2014
Synthesis of isoflavones by room-temperature nickel-
chenko A S, Mely Y, Burger A and Benhida R 2009
Efficient synthesis of ratiometric fluorescent nucleosides
featuring 3-hydroxychromone nucleobases Tetrahedron
65 7809
catalyzed cross-couplings of 3-iodo(bromo)chromones 36. (a) Rao M L N and Kumar A 2015 Pd-catalyzed
with arylzincs Mol. Divers. 18 245
cross-coupling study of bi-functional 3-bromo-4-
trifloxycoumarins with triarylbismuth reagents Tetrahe-
dron 71 5137; (b) Finet J-P and Fedorov A Y 2006 J.
Organomet. Chem. 691 2386; (c) De Ketelaere R F, Del-
beke F T and Van Der Kelen G P 1971 J. Organomet.
Chem. 30 365
31. Klier L, Bresser T, Nigst T A, Karaghiosoff K and
Knochel P 2012 Lewis acid-triggered selective zincation
of chromones, quinolones, and thiochromones: applica-
tion to the preparation of natural flavones and isoflavones
J. Am. Chem. Soc. 134 13584
32. Vasselin D A, Westwell A D, Matthews C S, Brad- 37. Wang J, Zhang Z, Wang W and Liu F 2013 One-
shaw T D and Stevens M F G 2006 Structural studies
on bioactive compounds. 40.(1) synthesis and biological
step synthesis of 5,6-diaryl pyridine-2(1H)-thiones from
isoflavones Org. Biomol. Chem. 11 2034
properties of fluoro-, methoxyl-, and amino-substituted 38. Varga M, Batori S, Kövari-Radkai M, Prohaszka-Nemet
3-phenyl-4H-1-benzopyran-4-ones and a comparison of
their antitumor activities with the activities of related 2-
phenylbenzothiazoles J. Med. Chem. 49 3973
I, Vitanyi-Morvai M, Böcskey Z, Bokotey S, Simon K
and Hermecz I 2001 Stability and chemical reactivity of
7-isopropoxyisoflavone (ipriflavone) Eur. J. Org. Chem.
3911
33. Tsoi Y-T, Zhou Z, Chan A S C and Yu W-Y 2010
Palladium-catalyzed oxidative cross-coupling reaction 39. CCDC-1412753 and CCDC-1412754 contains all crys-
of arylboronic acids with diazoesters for stereoselective
tallographic details for compounds 3.10 and 4.4 respec-
tively. It is available free of charge at www.ccdc.cam.
ac.uk/conts/-retrieving.html or can be ordered from the
following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ Fax:
(+44)1223-336-033 or deposit@ ccdc.cam.ac.uk
α
synthesis of (E)− ,β-diarylacrylates Org. Lett. 12 4506
34. Kurzwernhart A, Kandioller W, Bächler S, Bartel C,
Martic S, Buczkowska M, Mühlgassner G, Jakupec M
A, Kraatz H-B, Bednarski P J, Arion V B, Marko D,
Keppler B K and Hartinger C G 2012 Structure–activity