Convenient one-pot multicomponent strategy for the synthesis of 6-pyrrolylpyrimidines

Article abstract of DOI:10.1039/c4ra02891k

We have developed an easy method to construct diheteroaryls from α-aroylidineketene dithioacetals in a multicomponent manner. The reaction proceeded with high chemo/regioselectivity to yield 4-alkoxy-6-(4-aryl-1H- pyrrol-3-yl)pyrimidin-2-amines under mild

Full text of DOI:10.1039/c4ra02891k

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Convenient one-pot multicomponent strategy for
the synthesis of 6-pyrrolylpyrimidines†
Cite this: RSC Adv., 2014, 4, 29493
*
Pandi Dhanalakshmi and Sivakumar Shanmugam
We have developed an easy method to construct diheteroaryls from a-aroylidineketene dithioacetals in a
multicomponent manner. The reaction proceeded with high chemo/regioselectivity to yield 4-alkoxy-6-
(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines under milder conditions. It is found that a-aroylidineketene
dithioacetals (2) undergo cycloaddition with (p-tolylsulfonyl)methyl isocyanide (3) [TosMIC], guanidine
nitrate (5) and alcohol in the presence of NaH/THF to furnish the target 6-pyrrolylpyrimidines (8) in
excellent yields.
Received 1st April 2014
Accepted 9th June 2014
DOI: 10.1039/c4ra02891k
www.rsc.org/advances
Pyrimidines are bases present in nucleic acids and play signif-
a-Aroylidineketene dithioacetals 2 of aromatic substrates are
icant roles in medicinal chemistry1 by exhibiting antibacterial,2 very useful synthons for a variety of heterocycles. To examine
anti-inammatory,3 cytotoxicity,4 and anticancer5 properties. the reactivity of b-unsaturated ketones and push–pull alkenes
They have a long and distinguished history extending from the together, we synthesized several a-aroylidineketene dithioace-
day of their discovery to their current use in chemotherapy, HIV tals 2a–o by aldol condensation between aryl aldehydes and 4,4-
treatment and in other clinical applications. Interestingly, bis(methylthio)but-3-en-2-one
pyrrole derivatives also nd signicant applications in the eld reported procedure12 (Scheme 1 and Table 1).
of medicinal chemistry because of their pharmacological
Following our earlier report,15 3,3-bis(methylthio)-1-(4-aryl-
1 by following a previously
properties6 and as synthons for porphyrins7/boron-dipyrro- 1H-pyrrol-3-yl)prop-2-en-1-one 4 was synthesized selectively via
methanes (BODIPY)8 synthesis etc. Pyrimidine and pyrrole 1,3-dipolar cycloaddition by involving (p-tolylsulfonyl)methyl
heterocycles combined together as a single molecule could be isocyanide16 3 and 2 in the presence of NaH/THF at room
expected to exhibit excellent biological activity.
temperature (Scheme 2). Similarly, styrylpyrimidines 6 was
Over the past decade, a-oxoketene dithioacetals have synthesized by following a previously reported procedure by
emerged as versatile intermediates in organic synthesis and mixing guanidine nitrate 5 and 2 under reux condition
have found applications in the synthesis of substituted and (Scheme 2).17,18
fused aromatic heterocyclic frameworks.9,10
Utilizing the structural features of a-aroylidineketene
The a-aroylidineketene dithioacetals11 2 are ve-carbon 1,5- dithioacetal 2, we generated novel heterocyclic molecule 4-
bielectrophilic species, have dense and exible substitution alkoxy-6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines 8 in a multi-
patterns, and good leaving alkylthio groups open to SNV-type component fashion with excellent yields. To the best of our
reactions. The a-aroylidineketene dithioacetals 2 have two knowledge, no such study on the synthesis of a diheteroaryl core
different double bonds between C1–C2 (A) and C4–C5 (B). has been reported using this methodology.
Double bond A is a push–pull type anked by two electron
In continuation of our earlier work,15 compound 8a was
donating methyl sulfanyl and one electron withdrawing synthesized by considering the reaction as a test case to evaluate
carbonyl group, and B is anked by an electron withdrawing the cycloaddition of 3, 5 with 2a and methanol in a multicom-
carbonyl and aryl group (Fig. 1). Double bond A is more polar- ponent manner. Several reactions were tried to optimize the
ized than B because of the electron donating characteristics of reaction conditions (Scheme 3 and Table 2).
the two methyl sulfanyl groups and has the structural features
A model cycloaddition reaction between 3, 5 with 2a and
of a a,b-unsaturated carbonyl group with different reactivity methanol in the presence of NaH/THF at RT-70 ꢀC for 10 h was
toward addition/substitution reactions for the synthesis of
various heterocyclic compounds.
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai – 625 021, India. E-mail: shivazzen@mkuniversity.org
† Electronic supplementary information (ESI) available. CCDC 955689. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra02891k
Fig. 1 General structure of a-aroylidineketene dithioacetals 2.
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Table 2 Optimization of reaction conditions for the synthesis of 8a in
a multicomponent mannera
Entry
Bases
Solvents
Temp. (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
NaH
NaH
NaH
NaH
NaH
NaH
NaH
K2CO3
K2CO3
K2CO3
DBU
DBN
THF
THF
70
70
10
15
12
12
12
12
12
12
12
12
12
12
75a
75a
40b
20b
15b
<5b
<5b
Scheme 1 Synthesis of a-aroylidineketene dithioacetals 2a–o from 1.
Table 1 Synthesis of a-aroylidineketene dithioacetals 2a–o from 1
1,4-Dioxane
Benzene
Toluene
DMF
Xylene
Toluene
THF
1,4-Dioxane
THF
THF
110
100
110
120
140
110
70
110
70
70
Entry
Ar
Time (min)
Yieldb %
b
—
1
2
3
4
5
6
7
8
4-OMe–C6H4–
2,4-Cl2–C6H3–
3-Cl–C6H4–
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
30
30
45
45
30
40
30
30
40
30
30
45
90
60
60
90c
99
b
9
—
—
<5b
b
10
11
12
85
C6H5–
81c
88
b
—
2,4-F2–C6H3–
2-OMe,5-Br–C6H3–
4-Cl–C6H4–
3,4,5-OMe–C6H2–
3-OH–C6H4–
3,4-OMe–C6H3–
4-CH3–C6H4–
2 F–C6H4–
a
b
Isolated yields aer column chromatography. Starting material 2a
87
recovered.
99c
88c
87
9
10
11
12
13
14
15
89c
90c
92
were performed using other bases such as K2CO3, DBU and DBN
(entries 8–12, Table 2).
The cyclization was optimized with 8, which was obtained by
the cyclocondensation of 2a, 3, 5 and alcohol in a multicom-
ponent manner with excellent yields (Scheme 4). Ensuing
studies showed that the efficiency of the formation of this
product was highly dependent on solvent as well as the base.
Importantly, the reaction in NaH/THF yields 75% of 8a in a
highly chemo/regioselective manner. To explore the scope of
this novel strategy, we consecutively investigated the cycload-
dition of 2a–o with 3, 5 and alcohol by following the optimized
condition 8a–ad obtained in excellent yields 70–97% (Table 3).
The 1H NMR spectrum of 8a was taken as an example and the
chemical shis were analysed. The 1H NMR spectrum assigned
two singlets at d 3.66 and 3.74 ppm to two methoxy groups at C-4
and C-400, respectively. The free amino proton at C-2 position
appeared as a singlet at d 6.24 ppm and at the same time the NH
proton of the pyrrole ring displayed a broad singlet at d 11.11
ppm. We also noticed that the chemical shi appearing at d 5.58
ppm for the C-5 proton was shied slightly upeld compared
with the chemical shi of a simple pyrimidine molecule (d ꢁ
6.46 ppm). This upeld shi may be because of the shielding
effect of a pyrrole ring at C-6 position. The 13C NMR of 8a dis-
played fourteen signals with diagnostic signals at d 52.9 and
55.2 ppm assignable to two methoxy groups at C-4 and C-400,
respectively. In addition, to support analytical data, the struc-
ture of 8e was conrmed on the basis of single-crystal X-ray
structural analysis (Fig. 2).19
2-Furyl–
2-Thienyl–
5-Br–C5H3N–
87
86
82
a
Optimal reaction conditions: 1 (1 eq.), Ar-CHO (1.1 eq.), 10% NaOH
(1.5 eq.), ethanol (5 ml), water (1 ml), 10 ꢀC – RT, 30–90 min.
b
c
Isolated yields aer recrystallization. Compounds 2a, 2d, 2g, and
2k,13 2h and 2j14 are known.
Scheme 2 Synthesis of 4 and 6 by the cycloaddition of 2d with 3
and 5.
Scheme 3 Optimization of reaction conditions for the synthesis of 8a
in a multicomponent manner.
explored in our initial effort (entry 1, Table 2). Indeed, the
reaction proceeds to give the desired product 8a in good yield.
The yield of the product does not change, even when the reac-
tion continued up to 15 h (entry 2, Table 2). In contrast, reac-
tions occurring in other solvents, such as 1,4-dioxane, toluene,
benzene dimethylformamide (DMF) and xylene, proceed with
very poor yields, even with a prolonged reaction time (entries 3–
Scheme
4 Synthesis of 8a–ad in a multicomponent fashion by
7, Table 2). The cycloaddition did not occur when the reactions reacting 2 with 3, 4 and alcohol.
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Table 3 Synthesis of 8a–ad in a multicomponent fashion by reacting 2
with 3, 4 and alcohola
decomposition, all the triheteroaryl compounds 8y–ad were
obtained as a single product in very good yields. The R group
was appropriately xed as a methyl/ethyl at the C-4 position of 8.
The yield of the product 8a–ad varied on changing the substi-
tution by electron donating/withdrawing groups in the phenyl
ring. All other structures of 6-pyrrolylpyrimidines 8a–ad were
analysed by 1H and 13C NMR, and mass spectroscopy.
On the other hand, the 1,3-dipolar cycloaddition between 3
and 6 was employed in the presence of NaH/THF at RT for 2 h to
afford 8a in a very poor yield of 30% (Scheme 5). Subsequently,
4a was cyclized with guanidine nitrate 5 to afford 8a in 86%
yield (Scheme 5). Although compound 8a was obtained in good
yield from 2a via 4a, the cycloaddition proceeds in multi-steps.
To avoid multi-steps as well as processing time, we focused our
interest on the synthesis of 8a–ad in a multicomponent
manner.
A postulated reaction pathway for the formation of 4-alkoxy-
6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines 8a–ad is illustrated
(Scheme 6). To evaluate cycloaddition in a multicomponent
manner, 3, 5 with 2a was combined together in the presence of
NaH/THF at RT. Interestingly, 3 undergoes 1,3-dipolar cyclo-
addition selectively with double bond B of 2, followed by the
removal of the tosyl group to yield the corresponding 4. The 1,3-
dipolar cycloaddition did not proceed with the push–pull
alkene because the double bond A of 2 is more polarized than B
due to two electron donating methyl sulfanyls and one electron
Entry
Ar
R
Yieldb (%)
1
2
3
4
5
6
7
8
4-OMe–C6H4–
4-OMe–C6H4–
2,4-Cl2–C6H3–
2,4-Cl2–C6H3–
3-Cl–C6H4–
3-Cl–C6H4–
C6H5–
C6H5–
2,4-F2–C6H3–
2,4-F2–C6H3–
2-OMe,5-Br–C6H3–
2-OMe,5-Br–C6H3–
4-Cl–C6H4–
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
8v
8w
8x
8y
8z
8aa
8ab
8ac
8ad
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
75
87
85
89
97
95
85
83
80
82
70
72
87
89
84
87
77
78
85
82
88
86
88
90
83
85
87
87
78
75
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4-Cl–C6H4–
3,4,5-OMe–C6H2–
3,4,5-OMe–C6H2–
3-OH–C6H4–
3-OH–C6H4–
3,4-OMe–C6H3–
3,4-OMe–C6H3–
4-CH3–C6H4–
4-CH3–C6H4–
2-F–C6H4–
2-F–C6H4–
2-Furyl–
2-Furyl–
2-Thienyl–
2-Thienyl–
5-Br–C5H3N–
5-Br–C5H3N–
a
2a–o (1 eq.), NaH (2 eq.), TosMIC 3 (1.5 eq.), guanidine nitrate 5 (2 eq.),
alcohol (3 ml) (v/v), RT-70 ꢀC, 10 h. b Isolated yields.
The compounds 8e, 8f, 8v and 8d were isolated in highest
yields at the level of 97, 95, 90 and 89%, respectively. In addi-
tion, we synthesized few triheteroaryl derivatives 8y–ad by
introducing ve and six membered heterocycles, such as 2-furyl,
2-thienyl and pyridine, instead of a phenyl group at the C-400
position (Table 3, entries 25–30). Interestingly, without any
Scheme 5 Stepwise synthesis of 8a from 4a and 6.
Fig. 2 ORTEP representation of 8e.
Scheme 6 Plausible mechanism for the formation of 8.
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withdrawing carbonyl group, which makes C-1 electron rich.
Thus, the chemo/regioselecive formation of 4 was obtained on
the less polarized double bond B of 2. On the other hand, 5 did
not react with 2 at RT, and requires more vigorous conditions to
undergo Michael addition. Hence, the temperature was
increased gradually up to 70 ꢀC. During this period, alcohol was
added and replaced one MeSH group from 4, and then 5
undergoes Michael addition with push–pull alkene, which was
followed by intramolecular cyclization by the removal of one
MeSH group to afford 8 in excellent yields.
General procedure for the preparation of 1,1-bis-
(methylthio)-5-arylpenta-1,4-dien-3-one (2a–o). To a solution of
4,4-bis(methylthio)but-3-en-2-one 1 (1 eq.) in ethanol (5 ml),
NaOH (1.5 eq.) and aryl aldehyde (1.1 eq.) were added under
constant stirring. Aer the starting material was consumed by
TLC, the reaction mixture was poured onto ice water, and the
resulting solid was ltered and washed well with water (20 ml).
The solid material obtained was crystallized from ethanol to
furnish 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one 2a–o in
81–99% yield as a yellow solid.
(E)-1,1-Bis(methylthio)-5-(4-methoxyphenyl)penta-1,4-dien-3-
1
one (2a).13 Yellow solid; yield: 90% (3.1 g); mp 104–106 C; H
ꢀ
Conclusions
NMR (400 MHz, DMSO-d6): d 2.48 (s, 3H), 2.56 (s, 3H), 3.79 (s,
3H), 6.45 (s, 1H), 6.93 (d, J ¼ 16 Hz, 1H), 6.98 (d, J ¼ 8 Hz, 2H),
7.45 (d, J ¼ 15.9 Hz, 1H), 7.64 (d, J ¼ 8.8 Hz, 2H); 13C NMR (75
MHz, DMSO-d6) d 14.8, 17.2, 55.8, 114.2, 114.9, 126.2, 128.0,
130.3, 140.4, 161.3, 163.5, 183.7; IR (ATR KBr cell, cmꢂ1) 1581,
1644; LC-MS calcd m/z 280, found 281 [(M + 1)]+.
(E)-5-(2,4-Dichlorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-
one (2b). Pale yellow solid; yield: 99% (3.9 g); mp 126 ꢀC; 1H
NMR (400 MHz, DMSO-d6) d 2.40 (s, 3H), 2.45 (s, 3H), 5.29–5.31
(m, 1H), 5.55 (s, 1H), 6.17 (s, 1H), 7.43 (d, J ¼ 8.4 Hz, 1H), 7.50 (s,
1H), 7.59 (d, J ¼ 8.4 Hz, 1H), 7.69 (d, J ¼ 8.4 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) d 14.8, 17.3, 114.3, 128.4, 129.4, 129.9,
131.8, 132.3, 133.9, 135.0, 135.3, 166.3, 182.6; IR (ATR KBr cell,
cmꢂ1) 1500, 1650; HRMS (ESI-TOF) calcd for C13H12Cl2OS2Na
[M + Na]+ 340.9604, found 340.9601.
In summary, we described the development of efficient forma-
tion of 4-alkoxy-6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines 8a–
ad via a multicomponent approach with high chemo/regiose-
lectivity. The salient features of our method are the facile
introduction of various substitutions in a one-step process from
readily preparable starting materials 2a–o. The 6-pyrrolylpyr-
imidines 8a–ad were characterized by H and 13C NMR, mass
spectroscopy and single crystal X-ray analysis.
1
Experimental section
General experimental
Melting points were determined on a melting point apparatus
equipped with a thermometer, and were uncorrected. Unless
stated otherwise, solvents and chemicals were obtained from
commercial sources and used without further purication. The
1H and 13C NMR spectra of the new compounds were measured
at 400 MHz, 300 MHz and 100 MHz, 75 MHz using Bruker NMR
instrument in DMSO-d6, CDCl3 and chemical shis are reported
as d values (ppm) relative to tetramethylsilane. IR was measured
by a Thermo Nicolet 6700 FT IR Spectrometer using ATR
(attenuated total reection) KBr cell. Mass analysis was per-
formed by Agilent LC-MS instruments, and spectra were recor-
ded in positive and negative mode. Elemental analysis was
recorded on Thermonnigan ash 2000 organic elemental
CHNS analyser. Petroleum ether employed in column
chromꢀatographic purication refers to the fraction boiling at
40–60 C.
(E)-5-(3-Chlorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one
(2c). Pale yellow solid; yield: 85% (3 g); mp 136 ꢀC; 1H NMR (400
MHz, DMSO-d6) d 2.46 (s, 3H), 2.57 (s, 3H), 6.49 (s, 1H), 7.17 (d, J
¼ 16 Hz, 1H), 7.43–7.47 (m, 3H), 7.62–7.65 (m, 1H), 7.79 (s, 1H);
13C NMR (100 MHz, DMSO-d6) d 14.8, 17.3, 113.9, 127.3, 127.9,
129.9, 130.1, 131.2, 134.2, 137.8, 138.6, 165.2, 183.3; IR (ATR KBr
cell, cmꢂ1
13H13Cl2OS2Na [M + Na]+ 306.9994, found 306.9993.
)
1567, 1632; HRMS (ESI-TOF) calcd for
C
(E)-1,1-Bis(methylthio)-5-phenylpenta-1,4-dien-3-one
(2d).13
1
ꢀ
Pale yellow solid; yield: 81% (2.5 g); mp 150 C; H NMR (400
MHz, CDCl3) d 2.52 (s, 6H), 6.23 (s, 1H), 6.82 (d, J ¼ 16Hz, 1H),
7.35–7.40 (m, 3H), 7.55–7.57 (m, 2H), 7.61 (d, J ¼ 16 Hz, 1H); LC-
+
MS calcd m/z: 252, found 253 [(M + 1)] .
(E)-5-(2,4-Diuorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-
one (2e). Pale yellow solid; yield: 88% (3.1 g); mp 152–154 ꢀC; 1H
NMR (400 MHz, DMSO-d6) d 2.44 (s, 3H), 2.56 (s, 3H), 6.45 (s,
1H), 7.11 (d, J ¼ 16 Hz, 1H), 7.15–7.18 (m, 1H), 7.31–7.35 (m,
1H), 7.47 (d, J ¼ 15.6 Hz, 1H) 7.89 (q, J ¼ 15.6 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) d 14.3, 16.7, 104.3, 104.8, 112.2, 112.3,
112.5, 113.6, 119.4, 119.5, 130.5, 130.3, 130.4, 159.5, 161.6,
162.1, 164.1, 164.3, 165.1, 182.5; IR (ATR KBr cell, cmꢂ1) 1460,
1630; HRMS (ESI-TOF) calcd for C13H12F2OS2Na [M + Na]+
309.0195, found 309.0194.
(E)-5-(5-Bromo-2-methoxyphenyl)-1,1-bis(methylthio)penta-1,4-
dien-3-one (2f). Pale yellow solid; yield: 87% (3.9 g); mp 156–
158 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 2.45 (s, 3H), 2.56
(s, 3H), 3.86 (s, 3H), 6.44 (s, 1H), 7.04 (d, J ¼ 8.8 Hz, 1H), 7.15 (d,
J ¼ 16.4 Hz, 1H), 7.51 (d, J ¼ 8.8 Hz, 1H) 7.61 (d, J ¼ 15.6 Hz, 1H),
7.88 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 14.8, 17.2, 56.5,
General procedure for the synthesis of 4,4-bis(methylthio)
but-3-en-2-one 1. A solution of acetone (100 g, 1.721 mol) in
carbon disulphide (131 g, 1.721 mol) was added to a suspension
of sodium-tert-butoxide (331 g, 3.442 mol) in benzene (500 ml)
while maintaining the reaction temperature below 10 C. The
reaction mixture was stirred at RT for 3 h and methyl iodide
ꢀ
ꢀ
(489 g, 3.442 mol) was added at 10 C. The resulting reaction
mixture was stirred at RT overnight. Then, the reaction mixture
was diluted with ethyl acetate and washed twice with water. The
organic layer was dried over sodium sulphate, ltered and
concentrated in vacuum. The crude product was washed well
with hexane to give 172 g of 4,4-bis(methylthio)but-3-en-2-one
in 65% yield as a pale yellow crystalline solid. 1H NMR (400
MHz, CDCl3) d 2.20 (s, 3H), 2.45 (s, 3H), 2.47 (s, 3H), 6.04 (s, 1H);
LC-MS calcd m/z 162, found 163 [(M + 1)]+.
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112.8, 114.6, 126.1, 129.9, 130.1, 133.2, 134, 157.4, 165, 183.3; IR Hz, 1H), 7.81 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) d 14.8, 17.2,
(ATR KBr cell, cmꢂ1) 1469, 1642; HRMS (ESI-TOF) calcd for 113.3, 114.1, 115.7, 125.7, 127.4, 145.8, 151.7, 164.4, 183.1; IR
C
14H15BrO2S2Na [M + Na]+ 380.9595, found 380.9594.
(E)-5-(4-Chlorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one
(ATR KBr cell, cmꢂ1) 1465, 1642; HRMS (ESI-TOF) calcd for
C
11H12O2S2Na [M + Na]+ 263.0176, found 263.0173.
(2g).13 Yellow solid; yield: 99% (3.4 g); mp 144 ꢀC; 1H NMR (400
(E)-1,1-Bis(methylthio)-5-(thiphen-2-yl)-penta-1,4-dien-3-one
1
ꢀ
MHz, DMSO-d6) d 2.46 (s, 3H), 2.48 (s, 3H), 6.47 (s, 1H), 7.07 (d, J (2n). Brown solid; yield: 86% (2.7 g); mp 90 C; H NMR (400
¼ 16 Hz, 1H), 7.44–7.48 (m, 3H), 7.69 (d, J ¼ 8.4 Hz, 2H); 13C MHz, DMSO-d6) d 2.43 (s, 3H), 2.55 (s, 3H), 6.42 (s, 1H), 6.86 (d, J
NMR (100 MHz, DMSO-d6) d 14.3, 16.7, 113.4, 128.8, 128.9, ¼ 15.6 Hz, 1H), 7.48 (s, 1H), 7.49 (d, J ¼ 16 Hz, 1H), 7.59–7,61
129.7, 133.9, 134.3, 138.4, 164.4, 182.8; IR (ATR KBr cell, cmꢂ1), (m, 1H) 7.89 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 14.8, 17.2,
1598, 1646; LC-MS calcd m/z: 284, found 285 [(M +1)] +.
56.0, 113.8, 125.9, 128.1, 128.2, 129.3, 134.5, 138.8, 164.0, 183.9;
(E)-1,1-Bis(methylthio)-5-(3,4,5-trimethoxyphenyl)penta-1,4- IR (ATR KBr cell, cmꢂ1) 1567, 1634; HRMS (ESI-TOF) calcd for
dien-3-one (2h).14 Pale yellow solid; yield: 88% (3.7 g); mp 140–
142 ꢀC; 1H NMR (300 MHz, DMSO-d6) d 2.52 (s, 3H), 2.53 (s, 3H),
C
11H12OS3Na [M + Na]+ 278.9948, found 278.9945.
(E)-5-(5-Bromopyridin-3-yl)-1,1-bis(methylthio)penta-1,4-dien-3-
3.87 (s, 3H), 3.93 (s, 6H), 6.45 (s, 1H), 7.02 (s, 2H), 7.03 (d, J ¼ one (2o). Pale yellow solid; yield: 82% (3.3 g); mp 146 ꢀC; 1H
15.6 Hz, 1H), 7.26 (s, 1H), 7.42 (d, J ¼ 15.8 Hz, 1H); 13C NMR NMR (400 MHz, DMSO-d6): d 2.43 (s, 3H), 2.56 (s, 3H), 6.46 (s,
(100 MHz, DMSO-d6) d 14.3, 16.8, 55.9, 60.1, 105.6, 113.5, 127.3, 1H), 7.29 (d, J ¼ 16.00 Hz, 1H), 7.45 (d, J ¼ 16.00 Hz, 1H), 8.41 (s,
130.5, 139.1, 140.3, 153.1, 163.7, 183.1; IR (ATR KBr cell, cmꢂ1
)
3H), 8.66 (s, 1H), 8.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d
14.8, 17.2, 56.1, 112.2, 114.5, 121.1, 123.7, 128.3, 128.5, 131.9,
1578, 1640; LC-MS calcd m/z 340, found 341 [(M + 1)]+.
(E)-5-(3-Hydroxyphenyl)-1,1-bis(methylthio)penta-1,4-dien-3- 135.2, 158.4, 164.2, 183.9; IR (ATR KBr cell, cmꢂ1) 1165, 1488,
one (2i). Pale yellow solid; yield: 87% (2.9 g); mp 156–158 ꢀC; 1H 1590, 1646; HRMS (ESI-TOF) calcd for C12H12BrNOS2Na [M +
NMR (400 MHz, DMSO-d6): d 2.43 (s, 3H), 2.56 (s, 3H), 6.47 (s, Na]+ 351.9441, found 351.9449.
1H), 6.79 (d, J ¼ 10.0 Hz, 1H), 6.95 (d, J ¼ 15.6 Hz, 1H), 7.01 (s,
General procedure for the synthesis of 8a via 1,3-dipolar
1H), 7.08 (d, J ¼ 7.6 Hz, 1H), 7.19 (t, J ¼ 8 Hz, 1H), 7.37 (d, J ¼ 16 cycloaddition followed by cyclisation
Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d 14.7, 17.2, 114.1,
Step i: synthesis of 4 by reacting 2a with 3. To a stirred and
114.9, 117.6, 119.6, 128.4, 130.4, 136.8, 140.6, 158.2, 164.5, cleaned suspension of NaH (60% suspension in oil (0.10 g,
183.6; IR (ATR KBr cell, cmꢂ1) 1470, 1600; HRMS (ESI-TOF) 0.00427 mol)) in dry THF (2 ml) at 0 ꢀC, a mixture of TosMIC 3
calcd for C13H14O2S2Na [M + Na]+ 289.0333, found 289.0331.
(1.04 g, 0.0053 mol) and (E)-1-(4-methoxyphenyl)-5,5-bis(me-
(E)-5-(3,4-Dimethoxyphenyl)-1,1-bis(methylthio)penta-1,4-dien- thylthio)pent-1-en-3-one 2a (1 g, 0.00357 mol) was added in dry
3-one (2j).14 Pale yellow solid; yield: 89% (3.4 g); mp 125–127 ꢀC; THF (5 ml) over 15 min. The reaction mixture was then stirred at
1H NMR (400 MHz, DMSO-d6) d 2.42 (s, 3H), 2.56 (s, 3H), 3.78 (s, room temperature for 10 min. Aer completion of the reaction
3H), 3.80 (s, 3H) 6.44 (s, 3H), 6.95 (d, J ¼ 15.8 Hz, 1H), 6.97 (d, J (TLC), the mixture was carefully acidied with dilute acetic acid
¼ 8.31 Hz, 2H), 7.21 (d, J ¼ 10.5 Hz, 1H), 7.29 (s, 1H) 7.42 (d, J ¼ (pH 6.5) and extracted with ethyl acetate (3 ꢃ 20 ml). The
15.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 14.8, 17.2, 56.1, combined organic phase was washed with water (15 ml) and
110.5, 112.1, 114.1, 123.2, 126.3, 128.2, 140.8, 149.4, 151.1, brine (10 ml), and then dried over anhydrous Na2SO4 ltered
163.5, 183.7; IR (ATR KBr cell, cmꢂ1) 1565, 1637; UPLC-MS calcd and concentrated in vacuo. The crude product was puried by
m/z 310, found 311 [(M + 1)]+.
(E)-1,1-Bis(methylthio)-5-p-tolylpenta-1,4-dien-3-one (2k).13 Pale increasing amounts of ethyl acetate–petroleum ether (3 : 7) as
column chromatography using silica gel (60–120 mesh) with
1
1
ꢀ
yellow solid; yield: 90% (2.9 g); mp 130 C; H NMR (400 MHz, the eluent. Pale yellow solid; yield: 1 g (89%); mp 156 ꢀC; H
DMSO-d6): d 2.31 (s, 3H), 2.43 (s, 3H), 2.56 (s, 3H), 6.46 (s, 1H), NMR (400 MHz, DMSO-d6): d 2.18 (s, 3H), 2.37 (s, 3H), 3.76 (s,
7.00 (d, J ¼ 16.40 Hz, 1H), 7.21 (d, J ¼ 7.6 Hz, 2H), 7.43 (d, J ¼ 16 3H), 6.30 (s, 1H), 6.81 (s, 1H), 6.90 (d, J ¼ 8.60 Hz, 2H), 7.28 (d, J
Hz, 2H), 7.55 (d, J ¼ 8 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) d ¼ 8.60 Hz, 2H), 7.54 (s, 1H), 11.44 (s, 1H);13C NMR (100 MHz,
14.8, 17.2, 21.5, 114.1, 127.6, 128.5, 129.9, 132.7, 140.3, 140.4, DMSO-d6) d 14.6, 16.4, 55.6, 113.7, 114.1, 119.1, 124.1, 124.4,
164.1, 183.7; IR (ATR KBr cell, cmꢂ1) 1477, 1604; LC-MS calcd m/ 124.9, 128.8, 130.7, 158.3, 158.6, 182.3; LC-MS calcd m/z 319,
z 264, found 265 [(M + 1)]+.
found 320 [(M + 1)]+; IR (ATR KBr cell, cmꢂ1), 1474, 1599, 3355.
(E)-5-(2-Fluorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one
Step ii: synthesis of 8a by reacting 4 and 5. To a stirred and
(2l). Pale yellow solid; yield: 92% (3 g); mp 109 ꢀC; 1H NMR (400 cleaned suspension of sodium hydride (60% suspension in oil
ꢀ
MHz, DMSO-d6) d 2.45 (s, 3H), 2.57 (s, 3H), 6.47 (s, 3H), 7.15 (d, J 0.03 g, 0.00113 mol) in dry methanol (5 ml) at 0 C, guanidine
¼ 15.60 Hz, 1H), 7.23–7.29 (m, 2H), 7.42–7.46 (m, 1H), 7.53 (d, J nitrate 5 (0.23 g, 0.00188 mol) was added, and the reaction
¼ 16.4 Hz, 1H), 7.79 (t, J ¼ 8 Hz, 1H); 13C NMR (75 MHz, DMSO- mixture was allowed to stir at room temperature for 15 min.
d6) d 15.1, 17.2, 113.1, 115.9, 116.2, 123.2, 123.3, 124.3, 129.4, Then,
1-(4-(4-methoxyphenyl)-1H-pyrrol-3-yl)-3,3-bis(methyl-
129.8, 130.9, 131.1, 133.8, 159.7, 163.1, 166.1, 183.7; IR (ATR KBr thio)prop-2-en-1-one (0.3 g, 0.000939 mol) 4a was added and
cell, cmꢂ1) 1502, 1544, 1618; HRMS (ESI-TOF) calcd for allowed to reux for 8–10 h. The solvent was removed from the
C
13H13FOS2Na [M + Na]+ 291.0290, found 291.0289.
reaction mixture under reduced pressure. Then, water was
(E)-5-(Furan-2-yl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2m). added (5 ml) and the aqueous phase was extracted by ethyl
Low melting solid; yield: 87% (2.6 g); mp 109 ꢀC; 1H NMR (400 acetate. The organic layer was washed with water (2 ꢃ 5 ml) and
MHz, DMSO-d6) d 2.42 (s, 3H), 2.54 (s, 3H), 6.43 (s, 1H), 6.60 (bs, brine (2 ꢃ 5 ml) and dried over anhydrous Na2SO4, and then
1H), 6.75 (d, J ¼ 15.60 Hz, 1H), 6.87 (bs, 1H), 7.29 (d, J ¼ 15.60 ltered and concentrated. The crude product was subjected to
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column chromatography on silica gel (100–120 mesh) using
ethyl acetate–petroleum ether (8 : 2) to afford the pure
compound 8a in 86% (0.21 g) yield.
4-Methoxy-6-(4-(3-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-
amine) (8e). Colourless solid; yield: 97% (0.31 g); mp 122 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 3.69 (s, 3H), 5.65 (s, 1H), 6.24 (s,
2H), 6.95 (s, 1H), 7.22–7.32 (m, 5H), 11.34 (s, 1H); 13C NMR (100
MHz, DMSO-d6) d 52.6, 92.5, 119.2, 120.3, 121.0, 121.4, 125.4,
127.2, 127.8, 129.7, 132.6, 138.4, 162.9, 163.1, 169.9; IR (ATR KBr
cell, cmꢂ1), 1860, 2372, 3174; LC-MS calcd m/z 300, found 301
[(M + 1)]+. Anal. calcd for C15H13ClN4O: C, 59.91; H, 4.36; N,
18.63; found C, 59.87; H, 4.28; N, 18.57.
General procedure for the preparation of 4-alkoxy-6-(4-(4-
aryl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8a–ad). To a stirred
suspension of sodium hydride (60% suspension in oil (2 eq.)) in
dry THF (5 ml) at 0 ꢀC, 1,1-bis(methylthio)-5-arylpenta-1,4-dien-
3-one 2 (1 eq.), TosMIC 3 (1.5 eq.) and guanidine nitrate 5 (2 eq.)
was added, and the reaction mixture was stirred at RT for 5 min.
Later, alcohol (3 ml (v/v)) was added and allowed to reux for 10
h. The solvent was then removed from the reaction mixture
under reduced pressure, and the reaction mixture was extracted
with ethyl acetate. The organic layer was washed with water (2 ꢃ
5 ml) and brine (2 ꢃ 5 ml) and dried over anhydrous Na2SO4,
followed by ltration and concentration. The crude product was
subjected to column chromatography on silica gel (100–120
mesh) using ethyl acetate–petroleum ether (1 : 1) to afford the
pure compounds 8a–ad in excellent yields of 70–97%.
4-Methoxy-6-(4-(4-methoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-
amine (8a). Colourless solid; yield: 75% (0.24 g); mp 180 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 3.66 (s, 3H), 3.74 (s, 3H), 5.59 (s,
1H), 6.23 (s, 2H), 6.74 (s, 1H), 6.88 (d, J ¼ 8.8 Hz, 2H), 7.19 (d, J ¼
8.4 Hz, 2H), 7.25 (s, 1H), 11.11 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) d 52.9, 55.5, 92.7, 114.1, 118.8, 120.7, 121.0, 123.2,
129.1, 130.4, 158.1, 163.5, 163.6, 170.3; IR (ATR KBr cell, cmꢂ1),
1770, 2350, 3500; LC-MS calcd m/z 296, found 297 [(M + 1)]+.
Anal. calcd for C16H16N4O2: C, 64.85; H, 5.44; N, 18.91; found C,
64.82; H, 5.39; N, 18.89.
4-Ethoxy-6-(4-(4-methoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-
amine (8b). Colourless solid; yield: 87% (0.29 g); mp 142 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 1.17 (t, J ¼ 7.2 Hz, 3H), 3.75 (s, 3H),
4.15 (q, J ¼ 7.2 Hz, 2H), 5.58 (s, 1H), 6.17 (s, 1H), 6.74 (s, 1H),
6.88 (d, J ¼ 8.4 Hz, 2H), 7.19 (d, J ¼ 8.4 Hz, 2H), 7.25 (s, 1H),
11.11 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 14.9, 55.5, 61.1,
92.7, 114.0, 118.8, 120.7, 121.0, 123.2, 129.1, 130.4, 158.1, 163.5,
163.6, 169.9; IR (ATR KBr cell, cmꢂ1), 1890, 2360, 3379; LC-MS
calcd m/z 310, found 311 [(M + 1)]+. Anal. calcd for C17H18N4O2:
C, 65.79; H, 5.85; N, 18.05; found C, 65.72; H, 5.79; N, 18.01.
4-Methoxy-6-(4-(2,4-dichlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-
amine) (8c). Colourless solid; yield: 85% (0.27 g); mp 152 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 3.65 (s, 3H), 5.33 (s, 1H), 6.17 (s,
2H), 6.81 (s, 1H), 7.31–7.41 (m, 3H), 7.62 (s, 1H), 11.31 (s, 1H);
13C NMR (100 MHz, DMSO-d6) d 52.9, 91.0, 119.0, 119.9, 120.7,
121.6, 127.5, 129.1, 132.4, 133.9, 134.9, 135.2, 163.1, 163.5,
170.5; IR (ATR KBr cell, cmꢂ1), 1800, 2320, 3470; LC-MS calcd m/
z 335, found 336 [(M + 1)]+. Anal. calcd for C15H12Cl2N4O: C,
53.75; H, 3.61; N, 16.72; found C, 53.71; H, 3.59; N, 16.69.
4-Ethoxy-6-(4-(2,4-dichlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-
amine) (8d). Colourless solid; yield: 89% (0.28 g); mp 156 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 1.15–1.22 (t, J ¼ 7.2 Hz, 3H), 4.12
(q, J ¼ 7.2 Hz, 2H), 5.34 (s, 1H), 6.10 (s, 2H), 6.80 (s, 1H), 7.31–
7.41 (m, 3H), 7.61 (s, 1H), 11.30 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) d 14.8, 61.1, 91.2, 118.9, 119.9, 120.7, 121.7, 127.5,
129.1, 132.4, 133.9, 134.8, 135.3, 163.2, 163.4, 170.2; IR (ATR KBr
cell, cmꢂ1), 1683, 2300, 2900, 3320; UPLC-MS calcd. m/z 349,
found 350 [(M + 1)]+. Anal. calcd for C16H14Cl2N4O: C, 55.03; H,
4.04; N, 16.04; found C, 55.00; H, 4.01; N, 15.99.
4-Ethoxy-4-(4-(3-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-
amine) (8f). Colourless solid; yield: 95% (0.31 g); mp 186 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 1.19 (t, J ¼ 7.2 Hz, 3H), 4.18 (q, J ¼
7.2 Hz, 2H), 5.64 (s, 1H), 6.20 (s, 2H), 6.95 (s, 1H), 7.23–7.32 (m,
5H), 11.36 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 19.2, 65.4,
97.5, 123.9, 125.8, 126.1, 130.1, 131.9, 132.6, 134.5, 137.4, 143.2,
167.8, 174.3; IR (ATR KBr cell, cmꢂ1), 1840, 2370, 3320; LC-MS
calcd m/z 311, found 312 [(M + 1)]+. Anal. calcd for C16H15ClN4O:
C, 61.05; H, 4.80; N, 17.80; found C, 61.01; H, 4.75; N, 17.77.
4-Methoxy-6-(4-phenyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8g).
1
ꢀ
Colourless solid; yield: 85% (0.27 g); mp 174 C; H NMR (400
MHz, DMSO-d6): d 3.66 (s, 3H), 5.58 (s, 1H), 6.23 (s, 2H), 6.83 (s,
1H), 7.19 (s, 1H), 7.19–7.32 (m, 6H), 11.19 (s, 1H); 13C NMR (100
MHz, DMSO-d6) d 52.5, 92.3, 118.6, 120.2, 120.7, 123.0, 125.7,
128.0, 128.7, 136.2, 163.0, 163.1, 169.8; IR (ATR KBr cell, cmꢂ1),
1760, 2380, 3420; LC-MS calcd. m/z 266, found 267 [(M + 1)]+.
Anal. calcd for C15H14N4O: C, 67.65; H, 5.30; N, 21.04; found C,
67.59; H, 5.23; N, 21.00.
4-Ethoxy-6-(4-phenyl-1H-pyrrol-3-yl)pyrimidin-2-amine
(8h).
1
ꢀ
Colourless solid; yield: 83% (0.28 g); mp 126 C; H NMR (400
MHz, DMSO-d6): d 1.18 (t, J ¼ 7.2 Hz, 3H), 4.14 (q, J ¼ 7.2 Hz,
2H), 5.57 (s, 1H), 6.18 (s, 2H), 6.82 (s, 1H), 7.18–7.32 (m, 6H),
11.29 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 14.4, 60.6, 92.5,
118.6, 120.3, 120.7, 122.9, 125.8, 128.0, 128.7, 136.3, 163.1,
169.5; IR (ATR KBr cell, cmꢂ1), 1670, 2680, 3392; LC-MS calcd m/
z 280, found 281 [(M + 1)]+. Anal. calcd for C16H16N4O: C, 68.55;
H, 5.75; N, 19.99; found C, 68.50; H, 5.69; N, 19.91 (two carbon
signals merged with one another).
4-Methoxy-6-(2,4-diuorophenyl-1H-pyrrol-3-yl)pyrimidin-2-
1
ꢀ
amine (8i). Colourless solid; yield: 80% (0.27 g); mp 150 C; H
NMR (400 MHz, DMSO-d6): d 3.67 (s, 3H), 5.52 (s, 1H), 6.16 (s,
2H), 6.85 (s, 1H), 7.05–7.07 (m, 1H), 7.15–7.21 (m, 1H), 7.29–7.53
(m, 2H), 11.31 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 53.0, 91.3,
104.2, 104.6, 111.4, 111.6, 115.2, 120.1, 121.0, 121.6, 133.1,
158.3, 160.0, 161.4, 161.6, 163.5, 170.5; IR (ATR KBr cell, cmꢂ1),
1868, 2360, 3418; LC-MS calcd. m/z 302, found 303 [(M + 1)]+.
Anal. calcd for C15H12F2N4O: C, 59.60; H, 4.00; N, 18.53; found
C, 59.55; H, 3.93; N, 18.50.
4-Ethoxy-6-(2,4-diuorophenyl-1H-pyrrol-3-yl)pyrimidin-2-
1
ꢀ
amine (8j). Colourless solid; yield: 82% (0.29 g); mp 160 C; H
NMR (400 MHz, DMSO-d6): d 1.86 (t, J ¼ 7.2 Hz, 3H), 4.15 (q, J ¼
7.2 Hz, 2H), 5.52 (s, 1H), 6.10 (s, 2H), 6.84 (s, 1H), 7.02–7.07 (m,
1H), 7.15–7.21 (m, 1H), 7.29–7.35 (m, 2H), 11.30 (s, 1H); 13C
NMR (100 MHz, DMSO-d6) d 14.9, 61.1, 91.5, 104.6, 111.4, 111.7,
115.2, 120.1, 121.1, 121.6, 133.2, 158.3, 159.8, 161.4, 163.1,
163.2, 163.5, 170.2; IR (ATR KBr cell, cmꢂ1), 2360, 2989, 3436;
LC-MS calcd m/z 316, found 317 [(M + 1)]+. Anal. calcd for
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C16H14F2N4O: C, 60.75; H, 4.46; N, 17.71; found C, 60.71; H, MHz, DMSO-d6) d 14.4, 56.1, 60.8, 61.7, 95.0, 106.3, 118.1, 120.6,
4.43; N, 17.65.
120.9, 124.3, 131.1, 136.6, 152.8, 162.6, 162.8, 170.5; IR (ATR KBr
4-Methoxy-6-(4-(5-bromo-2-methoxyphenyl)-1H-pyrrol-3-yl)pyr- cell, cmꢂ1), 1790, 2400, 3298; LC-MS calcd m/z 370, found 371
imidin-2-amine (8k). Colourless solid; yield: 70% (0.22 g); mp [(M + 1)]+. Anal. calcd for C19H22N4O4: C, 61.61; H, 5.99; N,
182 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 3.52 (s, 3H), 3.74 (s, 3H) 15.13; found C, 61.50; H, 5.92; N, 15.04.
5.44 (s, 1H), 6.14 (s, 2H), 6.78 (s, 1H), 6.94 (d, J ¼ 8.8 Hz, 1H),
4-Methoxy-6-(4-(3-hydroxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-
7.28 (d, J ¼ 14.8 Hz, 2H), 7.42 (d, J ¼ 8.8 Hz, 1H), 11.17 (s, 1H); amine (8q). Colourless solid; yield: 77% (0.24 g); mp 148–150 ꢀC;
13C NMR (100 MHz, DMSO-d6) d 52.9, 55.8, 91.1, 111.9, 113.8, 1H NMR (400 MHz, DMSO-d6): d 3.67 (s, 3H), 5.62 (s, 1H), 6.23 (s,
117.9, 120.4, 121.7, 128.5, 130.7, 133.5, 156.8, 163.3, 170.5; IR 2H), 6.62 (d, J ¼ 8 Hz, 1H), 6.69 (s, 2H), 6.77 (s, 1H), 7.09 (t, J ¼ 8
(ATR KBr cell, cmꢂ1), 2360, 3362; LC-MS calcd. m/z 375, found Hz, 1H), 7.24 (s, 1H), 9.21 (s, 1H), 11.14 (s, 1H); 13C NMR (100
376 [(M + 1)]+. Anal. calcd for C16H15BrN4O2: C, 51.22; H, 4.03; N, MHz, DMSO-d6) d 20.9, 52.5, 92.4, 112.9, 115.7, 118.4, 119.6,
14.93; found C, 51.12; H, 3.99; N, 14.86.
120.2, 120.6, 121.9, 123.2, 127.1, 128.9, 129.7, 138.1, 143.5,
4-Ethoxy-6-(4-(5-bromo-2-methoxyphenyl)-1H-pyrrol-3-yl)pyr- 156.9, 162.9, 163.1, 169.8; IR (ATR KBr cell, cmꢂ1), 1650, 2200,
imidin-2-amine (8l). Colourless solid; yield: 72% (0.23 g); mp 3200; LC-MS calcd m/z 282, found 283 [(M + 1)]+. Anal. calcd for
170 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 1.18 (t, J ¼ 7.2 Hz, 3H)
C15H14N4O2: C, 63.82; H, 5.00; N, 19.85; found C, 63.74; H, 4.89;
3.52 (s, 3H), 4.14 (q, J ¼ 7.2 Hz, 2H), 5.44 (s, 1H), 6.07 (s, 2H), N, 19.78.
6.77 (s, 1H), 6.94 (d, J ¼ 8.8 Hz, 1H), 7.26 (d, J ¼ 12 Hz, 2H), 7.41
4-Ethoxy-6-(4-(3-hydroxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-
(d, J ¼ 8.8 Hz, 1H), 11.16 (s, 1H); 13C NMR (100 MHz, DMSO-d6) amine (8r). Colourless solid; yield: 78% (0.26 g); mp 126 ꢀC; H
d 14.9, 55.8, 60.9, 91.4, 111.9, 113.8, 117.8, 120.4, 121.9, 128.6, NMR (400 MHz, DMSO-d6): d 1.19 (t, J ¼ 7.2 Hz, 3H), 4.14 (q, J ¼
130.6, 133.4, 156.8, 163.4, 163.7, 170.1; IR (ATR KBr cell, cmꢂ1), 7.2 Hz, 2H), 5.60 (s, 1H), 6.18 (s, 2H), 6.61 (d, J ¼ 7.6 Hz, 1H),
1868, 2360, 3365; LC-MS calcd m/z 389, found 390 [(M + 1)]+. 6.72 (s, 1H), 6.76 (s, 1H), 7.07 (t, J ¼ 8 Hz, 1H), 7.23 (s, 1H), 9.21
Anal. calcd for C17H17BrN4O2: C, 52.46; H, 4.40; N, 14.39; found (s, 1H), 11.13 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 14.4, 60.6,
1
C, 52.41; H, 4.33; N, 14.30.
92.5, 112.9, 115.7, 118.4, 119.6, 120.3, 120.6, 123.2, 127.1, 128.9,
4-Methoxy-6-(4-(4-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2- 129.6, 137.6, 156.9, 163.0, 163.1, 169.5; IR (ATR KBr cell, cmꢂ1),
amine) (8m). Colourless solid; yield: 87% (0.28 g); mp 194 ꢀC; 1H 1750, 2300, 3470; LC-MS calcd m/z 296, found 297 [(M + 1)]+.
NMR (400 MHz, DMSO-d6): d 3.69 (s, 3H), 5.63 (s, 1H), 6.26 (s, Anal. calcd for C16H16N4O2: C, 64.85; H, 5.44; N, 18.91; found C,
2H), 6.89 (s, 1H), 7.25 (s, 1H), 7.34 (q, J ¼ 8.4 Hz, 4H), 11.34 (s, 64.79; H, 5.35; N, 18.83.
1H); 13C NMR (100 MHz, DMSO-d6) d 53.0, 92.9, 119.4, 120.8,
4-Methoxy-6-(4-(3,4-dimethoxyphenyl)-1H-pyrrol-3-yl)pyr-
121.5, 122.1, 128.4, 130.8, 135.6, 163.5, 163.6, 170.4; IR (ATR KBr imidin-2-amine (8s). Colourless solid; yield: 85% (0.27 g); mp
cell, cmꢂ1), 1867, 2369, 3420; LC-MS calcd m/z 300, found 301 182 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 3.66 (s, 6H), 3.74
[(M + 1)]+. Anal. calcd for C15H13ClN4O: C, 59.91; H, 4.36; N, (s, 3H), 5.66 (s, 1H), 6.23 (s, 2H), 6.79–6.81 (m, 2H), 6.86–6.93
18.63; found: C, 59.80; H, 4.27; N, 18.51 (two carbons merged (m, 2H), 7.25 (s, 1H), 11.13 (s, 1H); 13C NMR (100 MHz, DMSO-
with one another).
d6) d 52.5, 55.4, 55.5, 92.3, 111.7, 113.1, 118.3, 120.2, 120.5,
4-Ethoxy-6-(4-(4-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2- 120.8, 122.9, 128.8, 147.2, 148.2, 163.1, 169.9; IR (ATR KBr cell,
1
amine) (8n). Colourless solid; yield: 89% (0.3 g); mp 174 C; H cmꢂ1), 1790, 2490, 3220; LC-MS calcd. m/z 326, found 327 [(M +
ꢀ
NMR (400 MHz, DMSO-d6): d 1.20 (t, J ¼ 7.2 Hz, 3H), 4.17 (q, J ¼ 1)]+. Anal. calcd for C17H18N4O3: C, 62.57; H, 5.56; N, 17.17;
7.2 Hz, 2H), 5.62 (s, 1H), 6.20 (s, 2H), 6.89 (s, 1H), 7.24 (s, 1H), found C, 62.49; H, 5.45; N, 17.10.
7.34 (q, J ¼ 8.8 Hz, 4H), 11.25 (s, 1H); 13C NMR (100 MHz,
4-Ethoxy-6-(4-(3,4-dimethoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-
DMSO-d6) d 14.9, 61.2, 93.1, 119.4, 120.8, 121.5, 122.1, 128.4, 2-amine (8t). Colourless solid; yield: 82% (0.27g); mp 180 ꢀC; 1H
130.7, 135.6, 163.6, 163.6, 170.1; IR (ATR KBr cell, cmꢂ1), 1844, NMR (400 MHz, DMSO-d6): d 1.19 (t, J ¼ 7.2 Hz, 3H), 3.66 (s, 3H),
2360, 3387; LC-MS calcd m/z 314, found 315 [(M + 1)]+. Anal. 3.74 (s, 3H), 4.16 (q, J ¼ 7.2 Hz, 2H), 5.65 (s, 1H), 6.17 (s, 2H),
calcd for C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80; found C, 6.78–6.82 (m, 2H), 6.86–6.90 (m, 2H), 7.23 (s, 1H), 11.12 (s, 1H);
60.88; H, 4.72; N, 17.71 (two carbons merged with one another). 13C NMR (100 MHz, DMSO-d6) d 55.3, 55.5, 60.5, 92.5, 111.7,
4-Methoxy-6-(4-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl)pyr- 113.3, 118.3, 120.2, 120.5, 120.7, 122.9, 128.9, 147.2, 148.2,
imidin-2-amine (8o). Colourless solid; yield: 84% (0.26 g); mp 163.0, 163.2, 169.5; IR (ATR KBr cell, cmꢂ1), 1820, 2500, 3390;
1
168 C; H NMR (400 MHz, DMSO-d6): d 3.65 (s, 3H), 3.69 (s, LC-MS calcd m/z 340, found 341 [(M + 1)]+. Anal. calcd for
ꢀ
9H), 5.74 (s, 1H), 6.24 (s, 2H), 6.59 (s, 2H), 6.89 (s, 1H), 7.23 (s,
C18H20N4O3: C, 63.52; H, 5.92; N, 16.46; found C, 63.42; H, 5.83;
1H), 11.18 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 53.2, 56.1, N, 16.39.
60.9, 94.9, 106.3, 118.2, 120.7, 120.9, 124.3, 131.1, 136.7, 152.8,
4-Methoxy-6-(4-p-tolyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8u).
1
162.5, 170.8; IR (ATR KBr cell, cmꢂ1), 1800, 2370, 3495; LC-MS Colourless solid; yield: 88% (0.28 g); mp 150 C; H NMR (400
ꢀ
calcd m/z 356, found 357 [(M + 1)]+. Anal. calcd for C18H20N4O4: MHz, DMSO-d6): d 2.36 (s, 3H), 3.66 (s, 3H), 5.60 (s, 1H), 6.23 (s,
C, 60.66; H, 5.66; N, 15.72; found C, 60.59; H, 5.58; N, 15.62.
2H), 6.77 (s, 1H), 7.09–7.16 (m, 4H), 7.25 (s, 1H), 11.15 (s, 1H);
4-Ethoxy-6-(4-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl)pyr- 13C NMR (75 MHz, DMSO-d6) d 21.5, 52.9, 92.8, 118.9, 120.7,
imidin-2-amine (8p). Colourless solid; yield: 87% (0.28 g); mp 121.2, 123.4, 127.7, 130.3, 133.8, 135.3, 163.5, 163.6, 170.3; IR
170 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 1.18 (t, J ¼ 7.2 Hz, 3H), (ATR KBr cell, cmꢂ1), 1720, 2300, 3630; LC-MS calcd m/z 280,
3.69 (s, 9H), 4.16 (q, J ¼ 7.2 Hz, 2H), 5.72 (s, 1H), 6.21 (s, 2H), found 281 [(M + 1)]+. Anal. calcd for C16H16N4O: C, 68.55; H,
6.60 (s, 2H), 6.89 (s, 1H), 7.23 (s, 1H), 11.18 (s, 1H); 13C NMR (75 5.75; N, 19.99; found C, 68.48; H, 5.69; N, 19.90.
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LC-MS calcd m/z 272, found 273 [(M + 1)]+. HRMS (ESI-TOF)
calcd for C13H12N4OS [M + H]+ 273.0810, found 273.0812.
4-Ethoxy-6-(4-(thiophen-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine
4-Ethoxy-6-(4-p-tolyl-1H-pyrrol-3-yl)pyrimidin-2-amine
(8v).
1
ꢀ
Colourless solid; yield: 86% (0.29 g); mp 170–172 C; H NMR
(400 MHz, DMSO-d6): d 1.18 (t, J ¼ 6.8 Hz, 3H), 2.33 (s, 3H), 4.12
(q, J ¼ 7.2 Hz, 2H), 5.59 (s, 1H), 6.17 (s, 2H), 6.77 (s, 1H), 7.11 (d,
J ¼ 8 Hz, 2H), 7, 16 (d, J ¼ 7.6 Hz, 2H), 7.24 (s, 1H), 11.14 (s, 1H);
13C NMR (100 MHz, DMSO-d6) d 14.9, 21.2, 61.1, 92.9, 118.9,
120.7, 121.2, 123.4, 129.1, 133.8, 135.3, 163.6, 169.9; IR (ATR KBr
cell, cmꢂ1), 1854, 2330, 3570; LC-MS calcd m/z 294, found 295
[(M + 1)]+. Anal. calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03;
found C, 69.28; H, 6.10; N, 18.92.
4-Methoxy-6-(4-(2-uorophenyl)-1H-pyrrol-3-yl)pyrimidin-2-
amine (8w). Colourless solid; yield: 88% (0.28 g); mp 172 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 3.65 (s, 3H), 5.48 (s, 1H), 6.17 (s,
2H), 6.85 (s, 1H), 7.18 (d, J ¼ 7.6 Hz, 2H), 7.27–7.34 (m, 3H),
11.29 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 50.7, 89.8, 113.3,
113.6, 114.1, 117.6, 118.7, 119.5, 120.1, 122.3, 122.5, 125.5,
126.2, 130.1, 156.2, 159.5, 161.2, 168.5; IR (ATR KBr cell, cmꢂ1),
1633, 2360, 3380; LC-MS calcd m/z 284, found 285 [(M + 1)]+.
Anal. calcd for C15H13FN4O: C, 63.37; H, 4.61; N, 19.71; found C,
63.25; H, 4.52; N, 19.57.
1
ꢀ
(8ab). Colourless solid; yield: 87% (0.29 g); mp 140–142 C; H
NMR (400 MHz, DMSO-d6): d 1.21 (t, J ¼ 7.2 Hz, 3H), 4.16 (q, J ¼
7.6 Hz, 2H), 5.73 (s, 1H), 6.23 (s, 2H), 6.88 (s, 1H), 7.10 (d, J ¼ 4.6
Hz, 1H), 7.24 (s, 1H), 7.45–7.47 (m, 2H), 11.15 (s, 1H); 13C NMR
(100 MHz, DMSO-d6) d 14.9, 61.1, 92.7, 118.1, 119.2, 121.0,
121.1, 121.2, 125.5, 129.6, 136.9, 163.5, 163.7, 170.1; IR (ATR KBr
cell, cmꢂ1), 1559, 1645, 2209, 3406; LC-MS calcd m/z 286, found
287 [(M + 1)]+. Anal. calcd for C14H14N4OS: C, 58.72; H, 4.93; N,
19.57; found C, 58.65; H, 4.84; N, 19.47.
4-Methoxy-6-(4-(5-bromopyridin-3yl)-1H-pyrrol-3-yl)pyrimidin-
2-amine (8ac). Colourless solid; yield: 78% (0.25 g); mp 158–
160 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 3.74 (s, 3H), 5.82
(s, 1H), 6.22 (s, 2H), 7.13 (s, 1H), 7.30 (s, 1H), 7.94 (s, 1H), 8.51
(s, 2H), 11.43 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 53.2, 92.9,
118.0, 120.1, 120.6, 121.1, 122.0, 134.4, 137.9, 147.2, 147.8,
163.3, 163.6, 170.6; IR (ATR KBr cell, cmꢂ1), 1468, 1820, 2220,
3280, LC-MS calcd m/z 347, found 348 [(M + 1)]+. Anal. calcd for
C
14H12BrN5O. C, 48.57; H, 3.49; N, 20.23; found C, 48.44; H,
4-Ethoxy-6-(4-(2-uorophenyl)-1H-pyrrol-3-yl)pyrimidin-2-
1
ꢀ
3.41; N, 20.14.
amine (8x). Colourless solid; yield: 90% (0.3 g); mp 130 C; H
NMR (400 MHz, DMSO-d6): d 1.17 (t, J ¼ 7.2 Hz, 3H), 4.12 (q, J ¼
6.4 Hz, 2H), 5.47 (s, 1H), 6.12 (s, 2H), 6.84 (s, 1H), 7.13–7.18 (m,
2H), 7.28–7.33 (m, 3H), 11.30 (s, 1H); 13C NMR (75 MHz, DMSO-
d6) d 14.3, 61.8, 94.1, 115.3, 115.6, 116.9, 119.6, 120.5, 123.7,
127.9, 128.1, 131.9, 158.4, 161.7, 162.6, 162.9, 170.8; IR (ATR KBr
cell, cmꢂ1), 1795, 2288, 3400; LC-MS calcd m/z 298, found 299
[(M + 1)]+. HRMS (ESI-TOF) calcd for C16H15FN4O [M + H]+
299.1308, found 299.1307.
4-Ethoxy-6-(4-(5-bromopyridin-3yl)-1H-pyrrol-3-yl)pyrimidin-2-
amine (8ad). Colourless solid; yield: 75% (0.25 g); mp 126 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 1.23 (t, J ¼ 7.2 Hz, 3H), 4.21 (q, J ¼
7.2 Hz, 2H), 5.81 (s, 1H), 6.17 (s, 2H), 7.17 (s, 1H), 7.31 (s, 1H),
7.95 (s, 1H), 8.46 (s, 2H), 11.43 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) d 14.9, 61.2, 93.0, 118.0, 120.1, 120.5, 121.0, 121.9,
134.5, 137.8, 147.1, 147.8, 158.2, 163.6, 170.2; IR (ATR KBr cell,
cmꢂ1), 1440, 1860, 2300, 3320; LC-MS calcd. m/z 294, found 295
[(M + 1)]+. Anal. calcd for C15H14BrN5O: C, 50.02; H, 3.92; N,
19.44; found C, 49.92; H, 3.88; N, 19.32.
4-Methoxy-6-(4-(furan-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine
1
ꢀ
(8y). Pale yellow solid; yield: 83% (0.24 g); mp 168 C; H NMR
(400 MHz, DMSO-d6): d 3.73 (s, 3H), 5.80 (s, 1H), 6.30 (s, 2H),
6.45 (s, 1H), 6.53 (s, 1H), 7.01 (s, 1H), 7.29 (s, 1H), 7.56 (s, 1H),
11.30 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 53.1, 92.1, 107.2,
111.6, 113.2, 119.7, 120.9, 121.4, 141.5, 150.3, 163.1, 163.5,
170.6; IR (ATR KBr cell, cmꢂ1), 1420, 2300, 3100; LC-MS calcd m/
z 256, found 257 [(M + 1)]+. Anal. calcd for C13H12N4O2: C, 60.93;
H, 4.72; N, 21.86; found C, 60.79; H, 4.64; N, 21.79.
Acknowledgements
SS thanks UGC and DST–MRP, New Delhi for nancial assis-
tance. PD thanks UGC for meritorious fellowship. We thank
Prof. H. Surya Prakash Rao, Department of Chemistry, Pondi-
cherry University, Pondicherry for generous help in recording
spectra and helpful discussions. We thank Dr P. Thilagar,
Department of IPC, IISc Bangalore for helpful discussions and
analyzing the single crystal X-ray data.
4-Ethoxy-6-(4-(furan-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine
1
ꢀ
(8z). Pale yellow solid; yield: 85% (0.26 g); mp 126 C; H NMR
(400 MHz, DMSO-d6): d 1.22 (t, J ¼ 7.2 Hz, 3H), 4.22 (q, J ¼ 6.4
Hz, 2H), 5.79 (s, 1H), 6.26 (s, 2H), 6.44 (s, 1H), 6.54 (s, 1H), 7.01
(s, 1H), 7.29 (s, 1H), 7.56 (s, 1H), 11.29 (s, 1H); 13C NMR (100
MHz, DMSO-d6) d 14.4, 61.8, 94.8, 106.5, 110.9, 113.8, 118.8,
120.6, 120.8, 140.7, 149.5, 162.6, 162.7, 170.8, IR (ATR KBr cell,
cmꢂ1), 1485, 2239, 3465; LC-MS calcd m/z 270, found 271 [(M +
1)]+. Anal. calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73;
found C, 62.09; H, 5.17; N, 20.63.
Notes and references
1 (a) I. M. Kompis, K. Islam and L. K. Then, Chem. Rev., 2005,
105, 593–620; (b) M. A. P. Martins, W. Cunico,
C. M. P. Pereira, A. F. C. Flores, H. G. Bonacorso and
N. Zanatta, Curr. Org. Synth., 2004, 1, 391–403.
2 U. S. Gahlot, S. S. Rao, S. S. Dulawat, K. L. Ameta and
B. L. Verma, Anidad, 2003, 60, 558–562.
4-Methoxy-6-(4-(thiophen-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-
amine (8aa). Colourless solid; yield: 87% (0.28 g); mp 170–172
1
ꢀC; H NMR (400 MHz, DMSO-d6): d 3.70 (s, 3H), 5.74 (s, 1H),
3 A. M. Nofal, H. H. Fahmy, E. S. Zarea and W. El-Eraky, Acta
Pol. Pharm., 2011, 68, 507–517.
4 (a) C. C. Yit and N. P. Das, Cancer Lett., 1994, 82, 65–72; (b)
B. Jiang, C. G. Yang, W. N. Xiong and J. Wang, Bioorg. Med.
Chem., 2001, 9, 1149–1154.
6.27 (s, 2H), 6.89 (s, 1H), 7.08 (d, J ¼ 5.2 Hz, 1H), 7.24 (s, 1H),
7.42–7.47 (m, 2H), 11.16 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d
92.5, 118.2, 119.2, 121.1, 121.4, 125.5, 129.4, 129.6, 136.8, 163.5,
163.7, 170.5; IR (ATR KBr cell, cmꢂ1), 1597, 1800, 2365, 3400;
29500 | RSC Adv., 2014, 4, 29493–29501
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RSC Advances
5 (a) S. A. Rostom, H. M. Ashour, E. Abd and H. A. Razik, Arch. 11 (a) A. Thuiller and J. Vialle, Bull. Soc. Chim. Fr., 1962, 2182;
Pharm., 2009, 342, 299–310; (b) I. M. El-Deeb and S. H. Lee,
Bioorg. Med. Chem., 2010, 18, 3860–3874.
(b) B. Myrboh, C. V. Ashokan, H. Ila and H. Junjappa,
Synthesis, 1984, 50–51; (c) J. Tan, X. Xu, Y. Li and Q. Liu,
Angew. Chem., Int.Ed., 2009, 48, 2868–2872; (d) H. Wang,
Y. L. Zhao, C. Q. Ren, A. Diallo and Q. Liu, Chem.
Commun., 2011, 47, 12316–12318; (e) Y. Li, X. Xu, J. Tan,
C. Xia, D. Zhang and Q. Liu, J. Am. Chem. Soc., 2011, 133,
1775–1777.
6 (a) X. Rochais, V. Lisowski, P. Dallemagne and S. Rault,
Bioorg. Med. Chem., 2006, 14, 8162; (b) R. Di Santo,
R. Costi, M. Artico, G. Miele, A. Lavecchia, E. Novellino,
A. Bergamini, R. Cancio and G. Maga, ChemMedChem,
2006, 1, 1367; (c) L. Zeng, E. W. Miller, A. Pralle,
E. Y. Isacoff and C. J. Chang, J. Am. Chem. Soc., 2006, 128, 12 (a) A. Mathews and C. V. Ashokan, Tetrahedron, 2007, 63,
10; (d) B. R. Clark, R. J. Capon, E. Lacey, S. Tennant and
J. H. Gill, Org. Lett., 2006, 8, 701; (e) L. G. Regina,
7845–7849; (b) S. M. S. Chauhan and H. Junjappa,
Synthesis, 1974, 880–882.
R. Silverstri, M. Artico, A. Lavecchia, E. Novellino, 13 B. Myrboh, C. V. Ashokan, H. Ila and H. Junjappa, Synthesis,
O. Beffani, P. Turini and E. Agostinelli, J. Med. Chem.,
2007, 50, 92.
7 (a) Pyrroles, ed. R. A. Jones, Wiley, New York, 1992, part II; (b)
1984, 50–51.
14 S. Pandey, S. N. Suryawanshi, S. Gupta and
V. M. L. Srivastava, Eur. J. Med. Chem., 2004, 40, 751–756.
Comprehensive Heterocyclic Chemistry II, ed. D. S. C. Black, A. 15 H. S. P. Rao and S. Sivakumar, Beilstein J. Org. Chem., 2007, 3,
R. Katritzky, C. W. Rees and E. F. V. Scriven, Elsevier, Oxford,
1996, vol. 2, p. 39.
8 L. Aurore and B. Kevin, Chem. Rev., 2007, 107, 4891–4932.
9 (a) H. S. P. Rao and S. Sivakumar, J. Org. Chem., 2006, 71,
8715–8723; (b) H. S. P. Rao and S. Sivakumar, J. Org. Chem.,
31.
16 (a) D. van Leusen and A. M. Van leusen, Org. React., 2001, 57,
417–666; (b) P. Magnus, T. Gallagher, J. Schultz, Y. S. Or and
T. P. Ananthanarayan, J. Am. Chem. Soc., 1987, 109, 2706–
2711; (c) V. Padmavathy, T. Rathalakshmi, K. Mahesh and
A. V. N. Mohan, Indian J. Chem., 2008, 47B, 1707–1712.
2005,
70,
4524–4527;
(c)
P.
Dhanalakshmi,
S. Thimmarayaperumal and S. Shanmugam, RSC Advances, 17 W. Singh, A. K. Gupta, H. Ila and H. Junjappa, Synthesis,
2014, 4, 12028–12036. 1984, 516–518.
10 Reviews: R. K. Dieter, Tetrahedron, 1986, 42, 3029; 18 S. N. Suryawanshi, S. Kumar, R. Shivahare, S. Pandey,
H. Junjappa, H. Ila and C. V. Asokan, Tetrahedron, 1990,
46, 5423; P. Ling, B. Xiehe and L. Qun, Chem. Soc. Rev.,
2013, 42, 1251–1286.
A. Tiwari and S. Gupta, Bioorg. Med. Chem. Lett., 2013, 23,
5235–5238.
19 ESI.†
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RSC Adv., 2014, 4, 29493–29501 | 29501