The influence of ionic liquids on the Knoevenagel condensation of 1H-pyrrole-2-carbaldehyde with phenyl acetonitriles-cytotoxic 3-substituted-(1H-pyrrol-2-yl)acrylonitriles

Article abstract of DOI:10.1039/c3ra47418f

The Knoevenagel condensation of a series of substituted phenyl acetonitriles with 1H-pyrrole-2-carbaldehyde was examined in seven 1-butyl-3-methylimidazolium based ionic liquids and three protic ionic liquids. Of these [BMIM][Br] and [BMIM][OH], with cata

Full text of DOI:10.1039/c3ra47418f

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PAPER
The influence of ionic liquids on the Knoevenagel
condensation of 1H-pyrrole-2-carbaldehyde with
phenyl acetonitriles – cytotoxic 3-substituted-
(1H-pyrrol-2-yl)acrylonitriles†
Cite this: RSC Adv., 2014, 4, 19806
Ahmed Al Otaibi,a Christopher P. Gordon,a Jayne Gilbert,b Jennette A. Sakoffb
a
*
and Adam McCluskey
The Knoevenagel condensation of a series of substituted phenyl acetonitriles with 1H-pyrrole-2-
carbaldehyde was examined in seven 1-butyl-3-methylimidazolium based ionic liquids and three
protic ionic liquids. Of these [BMIM][Br] and [BMIM][OH], with catalytic piperidine, proved most
efficient affording 3-substituted-(1H-pyrrol-2-yl)acrylonitriles 3–17 in good to excellent yields (98%)
whilst utilisation of the protic ionic liquid propyl ammonium nitrate resulted in reduced yields (0–
66%). Screening of the 3-substituted-(1H-pyrrol-2-yl)acrylonitriles analogues 3–17 against a panel
of 11 cancer cell lines and one normal cell line allowed the identification of a series of compounds
with broad spectrum cytotoxicity, but more interestingly a significant degree of MCF-7 breast
cancer cell line specificity was evident with 6 (7 to >25 fold) and 13 (5.7 to >80 fold). Other
analogues show high level of efficacy against specific cell lines with 10 showing excellent activity
against MCF-7 (GI50 ¼ 1.7 mM) and A431 (GI50 ¼ 2.8 mM) cell lines. The most promising of the
compounds identified herein were the 4-CF3 substituted 10 and the 3,4-dichloro substituted 13 with
excellent activities against MCF-7 and A431 cell lines. The 3,4-dichloro-13 was a 0.56 mM potent
inhibitor of MCF-7 cell growth.
Received 9th December 2013
Accepted 27th March 2014
DOI: 10.1039/c3ra47418f
www.rsc.org/advances
technologies and the possible application of room temperature
ionic liquids to enhancing the outcome of simple synthetic
procedures.8–10
Introduction
Oen signicant enhancements in a compound's biological
activity can be accessed through a surprisingly small number of
robust chemical transformations.1 Arguably this small number
of highly utilized transformations should facilitate the greening
of drug and lead development pathways. However, in medicinal
chemistry access to pure compounds is of paramount impor-
tance and is oen pursued at the expense of green reaction
credentials.2–5 Within our own research efforts we have
routinely tolerated low yields and difficult purications to gain
access to the desired compounds.6,7 Recently our interest in
developing shorter and more environmentally friendly route to
focused compound libraries has seen us explore the application
of new technologies in this pursuit. Specically we have devel-
oped a considerable interest in emerging ow chemistry
In recent years our medicinal chemistry efforts have been
targeted in the areas of clathrin mediated endocytosis,11,12 the
synthesis of protein phosphatase 1 and 2A inhibitors for the
treatment of cancer and in the development of small molecule
anti-parasitic agents for the treatment of livestock.13–16 In all
instances we apply a focused compound library development –
biological screening iterative cycle approach to enhancing
compound activity. A cornerstone of these efforts has been the
application of the Knoevenagel condensation to the synthesis
of key precursors.8,11,17 These approaches are well documented
in the literature.18–24 These analogues were synthesized
under phase transfer catalysis (PTC) conditions using
PhCH2N(CH3)3(OH) as the PTC.9,24 While the reactions pro-
ceeded with moderate efficiency and yield, we believed that
ease of anion modication with room temperature ionic
liquids would allow us to select the most appropriate system
for rapid access to this compound series and potentially
simplify reaction work up by product precipitation.24–27 We
also viewed the Knoevenagel condensation as an ideal oppor-
tunity to probe the effects of different ionic liquids on the
reaction outcome.
aCentre for Chemical Biology, Chemistry, School of Environmental and Life Science,
The University of Newcastle, University Drive, Callaghan, New South Wales 2308,
Australia. E-mail: Adam.McCluskey@newcastle.edu.au; Fax: +61 (0)249 215472;
Tel: +61 (0)249 216486
bDepartment of Medical Oncology, Calvary Mater Hospital, Newcastle, New South
Wales 2308, Australia
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
See DOI: 10.1039/c3ra47418f
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Table
1
Reaction of pyrrole-2-carboxaldehyde (1) with phenyl
Results and discussion
acetonitrile (2) in the room temperature ionic liquids, [BMIM][PF6] and
[BMIM][OH], with and without added H2O
Our efforts commenced with the examination of one of the
archetypal room temperature ionic liquids, [BMIM][PF6] on the
Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with
phenyl acetonitrile (2). In the PhCH2N(CH3)3(OH) mediated
process required 5 h and 50 ꢀC and gave the expected products
in good yields (67–78%) across a range of substituted phenyl
acetonitriles (Scheme 1).24,25
Entry Ionic liquid/H2O Ratio
Temperature Time (h) Yield (%)
a
1
[BMIM][PF6]
—
50
5
5
5
—
—
—
—
—
—
5
2
3
4
5
[BMIM][PF6]/H2O (7 : 10) 50
[BMIM][PF6]/H2O (7 : 10) 70
[BMIM][PF6]/H2O (7 : 10) 90
[BMIM][PF6]/H2O (7 : 10) 90
[BMIM][PF6]/H2O (7 : 10) 90
5
24
48
18
72
18
19
24
5
In a related study Hangarge et al., reported the Knoevenagel
condensation of benzaldehyde and 3-methyl-1-phenylpyrazolin-
5-(4H)-one in ethyl ammonium nitrate (EAN) which proceeded
6
7
8
[BMIM][OH]
[BMIM][OH]
—
—
50
50
13
12
14
18
25
9
10
11
[BMIM][OH]/H2O (1 : 3) 50
[BMIM][OH]/H2O (1 : 15) 50
[BMIM][OH]/H2O (2 : 15) 50
[BMIM][OH]/H2O (3 : 7) 50
in 30 min in a 71% yield,28 while Verdıa et al. demonstrated the
´
facile condensation of aromatic aldehydes and active methylene
containing compounds in 1,3-dimethylimidazolium methyl 12
sulfate [MMIm][MSO4] containing up to 2.16% of water.29
a
‘—’ no product observed, reaction condition: pyrrole-2-
carboxaldehyde (165 mg, 1.74 mmol), phenyl acetonitrile (193 mL, 1.65
mmol) and (ionic liquids/H2O).
However our initial reaction using [BMIM][PF6] with pyrrole 2-
carboxaldhyde (1) and phenyl acetonitrile (2) under catalyst free
conditions gave no evidence of the Knoevenagel product (Table 1,
entry 1). Both the initial PTC and the [MMIm][MSO4] approaches
required added H2O,28,29 thus we examined the effect of added
H2O to [BMIM][PF6] at various temperatures. However, again,
research endeavours.9,10 These additional room temperature
ionic liquids included [BMIM]Br, [BMIM][BF4], [BMIM][NO3],
[BMIM][CH3COO], [BMIM][HCOO], and the protic ionic liquids
(pILs) EAN, propyl ammonium nitrate (PAN) and ethanol
ammonium nitrate (ETA), but in these examples we added
piperidine as our catalyst of choice. Interestingly the best yields
were noted for the traditional [BMIM]-based ionic liquids
(excepting [BMIM][NO3]) with yields $31%, while the protic
ionic liquids returned yields #30%. Of the pILs, PAN returned
the highest yield of 30% (Table 2, entry 7). Of these, in the
presence of piperidine, only [BMIM][NO3] showed no trace of
the desired product (Table 2, entry 5).
ꢀ
even with prolonged heating (2 days at 90 C), no reaction was
evident (Table 1, entries 2–6).
As we had previously reported on the use of base to catalyse
the Knoevenagel condensation,8,11,17 we rationalized that uti-
lisation of a basic ionic liquid would facilitate the desired
transformation. We thus examined the use of [BMIM][OH] in
our model Knoevenagel condensation of 1 and 2. While the
product was clearly observed, the yield was unacceptably low at
5–13% even aer 3 days at 50 ꢀC (Table 1, entries 7 and 8). The
addition of H2O to [BMIM][OH] had a modest effect on the
reaction outcome increasing the observed yield from 12 to 25%
(Table 1, entries 9–12).
Given the poor outcomes of the [BMIM][OH] mediated
condensation we repeated the experiment with the addition of
catalytic quantities of piperidine (see experimental). The effect
of added piperidine was stark with [BMIM][OH] subsequently
affording 85% of 3 (Table 2, entry 1) which compares very
favourably with the 73% yield obtained in the original PTC
approach.24 We believe that the additional activation associated
with [BMIM][OH] is a direct consequence of the OH-moiety
stabilising the imminium intermediate that arises from the
catalytic addition of piperidine to the pyrrole-2-carboxaldehyde
carbonyl moiety.30
Neither [BMIM][PF6] nor [BMIM][OH] allowed catalyst free
access to the desired 3-substituted-(1H-pyrrol-2-yl)acrylonitriles.
We thus examined a broader selection of room temperature
ionic liquids previously explored in other aspects of our
The catalytic role of piperidine was investigated by per-
forming the condensation reaction in aqueous medium (Table
3, entries 1 and 2). The results showed that 3% yield for the
desired product can be achieved with the use of water alone
Table 2 Knoevenagel condensation of pyrrole-2-carboxaldehyde (1)
with phenyl acetonitrile (2) in different ionic liquids and catalytic
piperidine
Entry
ILa
Yield (%)
1
2
3
4
5
6
7
8
9
10
[BMIM][OH]
[BMIM][Br]
[BMIM][BF4]
[BMIM][PF6]
[BMIM][NO3]
EAN
85
56
31
37
No reaction
24
30
18
29
35
PAN
ETA
[BMIM][CH3COO]
[BMIM][HCOO]
a
[BMIM][CH3COO], 1-butyl-3-methylimidazolium acetate; [BMIM]-
[HCOO], 1-butyl-3-methylimidazolium formate; [BMIM][OH], 1-methyl-
3-butylimidazolium hydroxide; EAN, ethyl ammonium nitrate; PAN,
propyl ammonium nitrate; ETA, ethanol ammonium nitrate. Reaction
condition: pyrrole-2-carboxaldehyde (165 mg, 1.74 mmol), phenyl
acetonitrile (193 mL, 1.65 mmol), H2O (10 mL) and Ionic liquids
(7 mL) at 50 ꢀC for 5 h.
Scheme 1 Model Knoevenagel condensation of pyrrole 2-carboxal-
dehyde with phenyl acetonitrile in an ionic liquid.
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Table
3 Reaction of pyrrole-2-carboxaldehyde (1) with phenyl
and did not require the use of specialist equipment to afford
access to the desired products.
acetonitrile (2) in aqueous solution and catalytic piperidine
As we had proposed that green chemistry approaches were
applicable to the development of biologically active
compounds, and we have previously reported the cytotoxicity of
related compounds,23 we examined compounds 3–17 for their
ability to inhibit the cell growth of a panel of cancer cell lines.
These cell lines were of colon (HT29, SW480), skin (A431), lung
(H460), ovarian (A2780), breast (MCF-7), prostate (Du145),
pancreatic (MIA), glioblastoma (SJ-G2, SMA, U87) and neuro-
blastoma (BE2-C) origin. One normal breast derived cell line,
MCF10A, was included as a measure of toxicity to healthy cells.
The outcomes of these screening studies are given in Table 5.
The screening data presented in Table 5 shows that
Aqueous
media
Temperature
(ꢀC)
Time
(h)
Yield
(%)
Entrya
Ratio
1
2
H2O
—
(7 : 10)
50
50
5
5
3
S.M.
[NH4+][OHꢂ]/H2O
a
S.M. ¼ start material, reaction condition: pyrrole-2-carboxaldehyde
(165 mg, 1.74 mmol), phenyl acetonitrile (193 mL, 1.65 mmol), H2O
(10 mL) and catalyst of piperidine.
while a quantitative recovery of the starting materials was
observed with the use of a 7 : 10 mixture of ammonium analogues 4, 5, 11 and 15 were inactive returning GI50 values
hydroxide : H2O. This strongly supports a key role for the IL in >50 mM across all cell lines examined. The parent phenyl
effecting the Knoevenagel condensation in these instances.
analogue, 3, was active against the HT29, MCF-7 and A2780;
Recently Zhao et al. reported the rapid and efficient Knoe- the 2-F substituted 7 against MCF-7; the 3-F substituted 8
venagel condensation catalysed by ultrasonic irradiation in against HT29, MCF-7 and A2780 cell lines. The remaining
protic ionic liquids,31 however our initial ndings presented in analogues 9, and 12 displayed modest; and 6, 10, 13, 16 and 17
Table 2 suggest that there is no requirement for ultrasonic displayed good activity across cell lines evaluated. Of the
irradiation in the presence of catalytic quantities of piperidine. brominated analogues only the p-Br (6) was active with GI50
Obviating the need for ultrasonic approaches brings this values ranging from 2.5 (MCF-7) to 40 mM (U87 and MIA) and a
synthetic procedure more within the realms of a traditional GI50 value of 51 mM against the normal breast cell line
synthetic or medicinal chemistry laboratory. However IL medi- (MCF0A), but the corresponding uorinated analogues, 7–10,
ated approaches would only be useful if they showed broad- were most active against the breast cancer cell line with GI50
spectrum applicability across a range of substituted phenyl values of 15, 9.8, 1.7 mM, respectively. The chlorinated
acetonitrile analogues. We thus set about examining the effect analogues, 12–14, displayed modest to good levels of broad
of various substituents and comparing the outcomes of the spectrum activity and retained specicity for the MCF-7 breast
subsequent Knoevenagel condensation in three ionic liquids: cancer cell line with GI50 values of 1.9 and 0.56 for 12 and 13
[BMIM][Br], [BMIM][OH] and PAN. This selection allowed mM, respectively. Interestingly while the introduction of a
comparison of the effects of traditional vs. protic ionic liquids second chlorine moiety with 12 and 13 gave rise to sub
on the reaction outcome. Previous SAR indicated that electro- micromolar potency against the MCF-7 cell line, this activity
negative moieties were advantageous to cytotoxic activity, thus was reduced signicantly in the case of the 3,5-dichloro
we initially examined a range of halogenated phenyl acetoni- substituent pattern (14, MCF-7 GI50 23 mM) compared with the
triles (3–14), along with the alkyne (15), nitrile (16) and nitro 3,4-dichloro substituent pattern of 13.
(17) acetonitriles.28 The outcomes of these studies are shown in
Table 4.
The uorine substitution pattern also had a marked effect on
cytotoxicity with the 2-F (7) active against only the breast cancer
Broadly speaking, the Knoevenagel condensation in the cell line MCF-7 with a GI50 ¼ 15 ꢁ 0.67 mM. Both the 3-F (8) and
selected room temperature ionic liquids detailed in Table 4, 4-F (9) analogues displayed a broad spectrum of cytotoxicity
leads to the expected 3-substituted-(1H-pyrrol-2-yl)acrylonitriles with 8 active against two cell lines (HT29, GI50 44 ꢁ 1.2 mM and
in moderate to excellent yields across all ionic liquids exam- MCF-7, 9.8 ꢁ 0.99 mM) and 9 active against seven cell lines
ined. With [BMIM][Br] the yields of 3-substituted-(1H-pyrrol-2- displaying a modest level of selectivity for the MCF-7 cell line. In
yl)acrylonitriles 3–17 ranged from 28% (9) to 98% (6); [BMIM]- keeping with the trend observed with the uorinated analogues,
[OH] from 34% (4) to 88% (5); and with PAN from 30% (3) to the 2-Cl analogue (11) was inactive; the 3-Cl analogue (12)
61% (8). Thus, the protic IL, PAN was the least effective at displays excellent activity across all cell lines excepting U87,
conducting this transformation. The lower yields (return of Du145, MIA and MCF10A (normal breast cells) with GI50 values
unreacted starting material) was most observable in those for the active cell lines ranging from 1.9 ꢁ 0.12 to 49 ꢁ 9 mM.
instances where the starting phenyl acetonitrile possessed an The activity of 12 was most notable with MCF-7 (1.9 ꢁ 0.12 mM)
ortho-substituent (Table 4, compounds 4 and 11), and also with and A431 (4.1 ꢁ 0.35 mM) both of which are oestrogen positive
the 4-F analogue (9), but this was offset in the disubstituted case cell lines. Introduction of a second chlorine substituent with 13
(Table 4, compound 13). The lower yields observed with PAN saw a signicant enhancement in cytotoxicity across essentially
may have been a consequence of the piperidine catalyst inter- all of the cell lines examined. In some cases there was a six fold
acting with residual free acid that may have been present or free potency enhancement relative to the mono-Cl analogue 12 with
NO3 anions as a result of extraneous H2O. No direct evidence of the H460 cell line (12 GI50 ¼ 36 ꢁ 1.3 vs. 13 GI50 ¼ 5.7 ꢁ 0.7 mM),
this was apparent in the 1H NMR of PAN. Overall this IL and this extra –Cl substituent resulted in sub micromolar
mediated approach was highly tolerant of simple substituents, potency against MCF-7 cell lines (0.56 ꢁ 0.03 mM). Both the
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Table 4 Reaction of pyrrole-2-carboxaldehyde with phenyl acetonitriles in [BMIM][Br] : H2O, [BMIM][OH] : H2O, and PAN : H2O (ratio of ionic
liquid to H2O is 7 mL : 10 mL) at 50 ꢀC, 5 h with catalytic piperidine
Phenyl acetonitrile
Product
[BMIM][Br]b yield (%)
[BMIM][OH]b yield (%)
PANb yield (%)
56
85
30
44
40
98
34
88
77
S.M.a
59
53
71
59
28
90
68
68
54
81
51
61
S.M.
46
42
79
89
55
45
72
S.M.
60
65
93
77
75
80
66
55
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Table 4 (Contd.)
Phenyl acetonitrile
Product
[BMIM][Br]b yield (%)
[BMIM][OH]b yield (%)
PANb yield (%)
60
63
58
58
70
48
a
S.M. ¼ start material, reaction condition: pyrrole-2-carboxaldehyde (165 mg, 1.74 mmol), with phenyl acetonitriles (193 mL, 1.65 mmol), H2O (10
b
mL) and ionic liquid (7 mL). ¼ [BMIM][Br] : H2O, [BMIM][OH] : H2O, and PAN : H2O (ratio of ionic liquid to water is 7 mL : 10 mL).
ethynyl (15) and nitro (17) display moderate levels of cytotoxicity from Sigma-Aldrich, all solvents were re-distilled from glass
across most cell lines examined.
prior to use.
1H and 13C NMR spectra were recorded on a Bruker Avance™
AMX 400 MHz spectrometer at 400 and 101 MHz, respectively.
Chemical shis (d) are reported in parts per million (ppm)
measured relative to the internal standards, and coupling
constants (J) are expressed in Hertz (Hz). Mass spectra were
recorded on a Shimadzu LCMS 2010 EV using a mobile phase of
1 : 1 acetonitrile : H2O with 0.1% formic acid.
¨
Conclusion
The Knoevenagel condensation of 1H-pyrrole-2-carbaldehyde
with a range of phenyl acetonitriles proceeded smoothly and
in excellent yields (up to 98%) in [BMIM] based ionic liquids
([BMIM][OH] and [BMIM][Br]) but only with added catalytic
piperidine. The corresponding condensations in the pIL,
PAN gave consistently lower isolated yields, typically between
30–66% although in a number of cases no product was
observed. It is conceivable that this was a function of the
catalytic piperidine interacting with either residual HNO3 or
free NO3 in PAN.
General method for synthesis of (Z)-2-phenyl-3-(1H-pyrrol-2-yl)
acrylonitrile (3)
1H-Pyrrole-2-carbaldehyde (1) (165 mg, 1.74 mmol) was added
to vigorously stirred H2O (10 mL) and heated to 50 C upon
ꢀ
Screening of the 3-substituted-(1H-pyrrol-2-yl)acrylonitriles
analogues 3–17 against a panel of 11 cancer cell lines and one
normal cell line allowed the identication of a series of
compounds with broad spectrum cytotoxicity, but more inter-
estingly that a signicant degree of MCF-7 breast cancer cell line
specicity was evident with 6 (7–>25 fold) and 13 (5.7–82 fold).
Other analogues show high level of efficacy against specic cell
which it dissolved. Phenyl acetonitrile (2) (193 mg, 1.65
mmol) was then slowly added forming a suspension and then
piperidine (2 drops, catalytic) was added. Heating was
continued at 50 ꢀC and once a clear solution was evident,
typically 5–10 min, the ionic liquid (7 mL) was added drop-
wise. The reaction vessel was then sealed and the mixture
stirred at 50 ꢀC for 5 h. The reaction solution was ltered hot,
washed with warm H2O and dried under vacuum to yield a
solid. The crude solid was recrystallised from EtOH to afford
compound (Z)-2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile (3) as a
brown solid.
lines with 10 showing excellent activity against MCF-7 (GI50
1.7 mM) and A431 (GI50 ¼ 2.8 mM) cell lines.
¼
These data suggest that ionic liquids do facilitate ease of
access to a range of cytotoxic 3-substituted-(1H-pyrrol-2-yl)
acrylonitriles and that these analogues display an interesting
breadth of cytotoxic activity and that with further development
may produce signicantly more potent potential development
candidates. The most promising of the compounds identied
herein are the 4-CF3 substituted 10 and the 3,4-dichloro
substituted 13 with excellent activities against MCF-7 and A431
cell lines. The 3,4-dichloro-13 was a 0.56 mM potent inhibitor of
MCF-7 cell growth.
MP 93–94 ꢀC; IR n(cmꢂ1): 3396, 2206, 1600, 1588, 1129, 753,
729, 681, 588, 484; 1H NMR (CDCl3): d 9.80 (brs, 1H), 7.61–7.55
(m, 2H), 7.44–7.38 (m, 3H), 7.36–7.29 (m, 2H), 7.10–7.04 (m,
1H), 6.74–6.66 (m, 1H), 6.37–6.32 (m, 1H); 13C NMR (101 MHz,
CDCl3): d 134.0, 131.4, 129.2, 128.3, 127.9, 125.1, 124.1, 120.8,
119.3, 110.9, 101.5.
(Z)-2-(2-Bromophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(4).
Synthesised using the general procedure as described for (3)
from 1H-pyrrole-2-carbaldehyde (1) and 2-bromophenylaceto-
nitrile to afford 4 as a light yellow solid.
Experimental
MP 122–123 ꢀC; IR n(cmꢂ1): 3309, 2205, 1596, 1139, 731, 596,
All reagents were purchased from Sigma-Aldrich, Matrix Scien- 444. 1H NMR (CDCl3): d 9.99 (brs, 1H), 7.79 (dd, J ¼ 8.0, 1.2 Hz,
tic or Lancaster Synthesis and were used without purication. 1H), 7.57–7.45 (m, 2H), 7.40 (s, 1H), 7.41–7.32 (m, 1H), 7.27–7.20
With the exception of THF (anhydrous >99%) obtained (m, 1H), 6.84–6.77 (m, 1H), 6.53–6.46 (m, 1H). 13C NMR (CDCl3):
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d 137.5, 135.7, 133.8, 131.0, 130.1, 128.1, 127.4, 124.5, 123.0,
120.1, 119.6, 110.9, 100.7.
(Z)-2-(3-Bromophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(5).
Synthesised using the general procedure as for the synthesis of
(3) from 1H-pyrrole-2-carbaldehyde (1) and 3-bromophenylace-
tonitrile to afford 5 as a brown solid.
MP 12–22 ꢀC; IR n(cmꢂ1): 3309, 2205, 1597, 1430, 1139, 731,
1
596, 444; H NMR (CDCl3): d 9.79 (brs, 1H), 7.71 (t, J ¼ 1.9 Hz,
1H), 7.52–7.47 (m, 1H), 7.47–7.42 (m, 1H), 7.39 (s, 1H), 7.31–7.27
(m, 1H), 7.09 (q, J ¼ 2.6 Hz, 1H), 6.73 (t, J ¼ 3.7 Hz, 1H), 6.40–
6.33 (m, 1H); 13C NMR (CDCl3): d 136.2, 132.2, 131.2, 130.7,
127.9, 127.6, 124.8, 123.8, 123.4, 120.4, 120.1, 111.2, 99.8.
(Z)-2-(4-Bromophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(6).
Synthesised using the general procedure as for the synthesis of
(3) from 1H-pyrrole-2-carbaldehyde (1) and 4-bromophenylace-
tonitrile to afford 6 as a yellow solid.
MP 123–124 ꢀC; IR n(cmꢂ1): 3374, 2213, 1487, 1131, 817, 739,
594, 489; 1H NMR (CDCl3): d 9.77 (brs, 1H), 7.53 (d, J ¼ 8.6 Hz,
2H), 7.44 (d, J ¼ 8.6 Hz, 2H), 7.38 (s, 1H), 7.11–7.06 (m, 1H),
6.74–6.66 (m, 1H), 6.40–6.32 (m, 1H); 13C NMR (101 MHz,
CDCl3): d 133.1, 132.3, 131.6, 127.7, 126.6, 124.6, 122.2, 120.4,
119.8, 111.2, 100.3.
(Z)-2-(2-Fluorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(7).
Synthesised using the general procedure as for the synthesis of
(3) from 1H-pyrrole-2-carbaldehyde (1) and 2-uo-
rophenylacetonitrile to afford 7 as a brown solid.
MP 100–102 ꢀC; IR n(cmꢂ1): 3409, 2205, 1603, 1125, 740, 677;
1H NMR (CDCl3): d 9.83 (brs, 1H), 7.57–7.47 (m, 2H), 7.35–7.06
(m, 4H), 6.75–6.65 (m, 1H), 6.40–6.31 (m, 1H); 13C NMR (CDCl3):
d 159.7 (d, J ¼ 248.7 Hz), 135.9 (d, J ¼ 9.4 Hz), 129.7 (d, J ¼ 8.6
Hz), 129.1 (d, J ¼ 2.5 Hz), 127.8, 124.8 (d, J ¼ 3.7 Hz), 124.6,
122.4 (d, J ¼ 10.7 Hz), 120.6, 119.9, 116.6 (d, J ¼ 22.2 Hz), 111.0,
95.9 (d, J ¼ 2.2 Hz).
(Z)-2-(3-Fluorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(8).
Synthesised using the general procedure described for (3) from
1H-pyrrole-2-carbaldehyde (1) and 3-uorophenylacetonitrile to
afford 8 as a green solid.
MP 104–107 ꢀC; IR n(cmꢂ1): 3396, 2208, 1583, 1407, 1121,
745, 594, 522; 1H NMR (CDCl3): d 9.79 (s, 1H), 7.43–7.34 (m, 3H),
7.30–7.27 (m, 0H), 7.09 (td, J ¼ 2.8, 1.4 Hz, 1H), 6.73 (dd, J ¼ 3.7,
1.6 Hz, 1H), 6.37 (dt, J ¼ 3.7, 2.4 Hz, 1H); 13C NMR (101 MHz,
CDCl3): d 163.3 (d, J ¼ 245.2 Hz), 136.3 (d, J ¼ 8.1 Hz), 132.1,
130.8 (d, J ¼ 8.5 Hz), 127.6, 124.7, 120.9 (d, J ¼ 2.9 Hz), 120.4,
120.0, 115.1 (d, J ¼ 21.2 Hz), 111.9 (d, J ¼ 23.4 Hz), 111.2, 100.2
(d, J ¼ 2.9 Hz).
(Z)-2-(4-Fluorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(9).
Synthesised using the general procedure as described for (3)
from 1H-pyrrole-2-carbaldehyde (1) and 4-uorophenylacetoni-
trile to afford 9 as a light yellow solid.
MP 10–103 ꢀC; IR n(cmꢂ1): 3393, 2208, 1593, 1122, 857, 745,
1
687; H NMR (CDCl3): d 9.76 (s, 1H), 7.54 (dd, J ¼ 8.7, 5.2 Hz,
2H), 7.32 (s, 1H), 7.16–7.04 (m, 3H), 6.69 (s, 1H), 6.35 (q, J ¼ 2.8
Hz, 1H); 13C NMR (101 MHz, CDCl3): d 162.7 (d, J ¼ 246.7 Hz),
131.3 (d, J ¼ 22.1 Hz), 130.3 (d, J ¼ 3.4 Hz), 127.7, 126.9 (d, J ¼
8.2 Hz), 124.2, 120.6, 119.3, 116.2 (d, J ¼ 21.9 Hz), 111.0, 100.4.
(Z)-3-(1H-Pyrrol-2-yl)-2-(4-(triuoromethyl)phenyl)acrylonitrile
(10). Synthesised using the general procedure as
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described for (3) from 1H-pyrrole-2-carbaldehyde (1) and 132.9, 131.7, 127.8, 124.8, 124.7, 121.9, 120.4, 119.9, 111.2,
4-triuoromethylphenylacetonitrile to afford 10 as a yellow 100.6, 83.2, 78.8.
solid.
(Z)-2-(1-Cyano-2-(1H-pyrrol-2-yl)vinyl)benzonitrile (16). Syn-
MP 149–150 ꢀC; IR n(cmꢂ1): 3389, 2205, 1590, 1167, 1111, thesised using the general procedure as described for (3) from
1
833, 752, 583; H NMR (CDCl3): d 9.83 (brs, 1H), 7.72–7.62 (m, 1H-pyrrole-2-carbaldehyde (1) and 2-cyanophenylacetonitrile to
4H), 7.48 (s, 1H), 7.16–7.09 (m, 1H), 6.80–6.73 (m, 1H), 6.42–6.35 afford 16 as a green solid.
(m, 1H); 13C NMR (CDCl3): d 137.6 (q, J ¼ 1.4 Hz), 132.8, 130.0 (q,
MP 148–149 ꢀC; IR n(cmꢂ1): 3420, 2218, 2199, 1605, 1403,
J ¼ 32.6 Hz), 127.6, 126.2 (q, J ¼ 3.8 Hz), 125.2, 124.0 (q, J ¼ 1333, 740, 572; 1H NMR (CDCl3): d 9.81 (brs, 1H), 7.75 (d, J ¼ 7.7
270.3 Hz), 120.6, 120.3, 111.4, 99.7.
Hz, 1H), 7.68–7.61 (m, 2H), 7.56 (s, 1H), 7.43 (ddd, J ¼ 7.7, 5.9,
(Z)-2-(2-Chlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(11). 2.7 Hz, 1H), 7.14 (q, J ¼ 2.7 Hz, 1H), 6.85–6.81 (m, 1H), 6.41–6.37
Synthesised using the general procedure as described for (3) (m, 1H); 13C NMR (CDCl3): d 138.2, 137.3, 134.7, 133.4, 129.2,
from
1H-pyrrole-2-carbaldehyde
(1)
and
2-chlor- 128.5, 127.2, 125.6, 121.1, 120.0, 117.9, 111.6, 110.0, 97.2.
ophenylacetonitrile to afford 11 as a brown solid.
(Z)-2-(4-Nitrophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (17). Syn-
MP 110–112 ꢀC; IR n(cmꢂ1): 3309, 2207, 1595, 1141, 730, 595; thesised using the general procedure as described for (3) from
1H NMR (CDCl3): d 9.87 (brs, 1H), 7.47–7.43 (m, 1H), 7.42–7.38 1H-pyrrole-2-carbaldehyde (1) and 4-nitrophenylacetonitrile to
(m, 1H), 7.34–7.29 (m, 2H), 7.18 (s, 1H), 7.12–7.06 (m, 1H), 6.72– afford 17 as a brown solid.
6.65 (m, 1H), 6.40–6.32 (m, 1H); 13C NMR (101 MHz, CDCl3): d
MP 130–133 ꢀC; IR n(cmꢂ1): 3368, 2208, 1507, 1576, 1327,
137.5, 133.8, 133.1, 130.6, 130.5, 129.9, 127.5, 124.5, 120.2, 1034, 757, 683, 482; 1H NMR (CDCl3): d 9.87 (brs, 1H), 8.27 (d, J
119.6, 110.9, 98.9.
¼ 8.9 Hz, 2H), 7.72 (d, J ¼ 8.9 Hz, 2H), 7.55 (s, 1H), 7.22–7.10 (m,
(Z)-2-(3-Chlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(12). 1H), 6.88–6.73 (m, 1H), 6.47–6.29 (m, 1H); 13C NMR (CDCl3): d
Synthesised using the general procedure as described for (3) 147.1, 140.5, 133.8, 127.6, 126.2, 125.4, 124.6, 121.8, 120.0,
from 1H-pyrrole-2-carbaldehyde (1) and 3-chlor- 111.8, 98.8.
ophenylacetonitrile to afford 12 as a yellow solid.
MP 111–112 ꢀC; IR n(cmꢂ1): 3386, 2212, 1605, 1528, 1398,
1132, 1039, 732, 681, 590; 1H NMR (CDCl3): d 9.79 (brs, 1H),
7.62–7.51 (m, 1H), 7.50–7.42 (m, 2H), 7.40 (s, 1H), 7.34 (t, J ¼ 7.8
Hz, 1H), 7.13–7.06 (m, 1H), 6.76–6.69 (m, 1H), 6.40–6.33 (m,
1H); 13C NMR (CDCl3): d 135.9, 135.3, 132.1, 130.4, 128.2, 127.6,
125.0, 124.8, 123.3, 120.4, 120.1, 111.2, 100.0.
(Z)-2-(3,4-Dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(13). Synthesised using the general procedure as described for
(3) from 1H-pyrrole-2-carbaldehyde (1) and 3,4-dichlor-
ophenylacetonitrile to afford 13 as a yellow solid.
Acknowledgements
AAO thanks the Saudi Arabian government for the provision of a
PhD scholarship. AM acknowledges project funding from the
Australian Research Council, and CPG is the recipient of an
Australian Research Council DECRA fellowship.
References
MP 140–141 ꢀC; IR n(cmꢂ1): 3416, 2200, 1604, 1125, 748, 590,
492; 1H NMR (CDCl3): d 9.78 (brs, 1H), 7.65 (d, J ¼ 2.2 Hz, 1H),
7.47 (d, J ¼ 8.5 Hz, 1H), 7.41 (d, J ¼ 2.3 Hz, 1H), 7.38 (s, 1H),
7.15–7.07 (m, 1H), 6.77–6.72 (m, 1H), 6.40–6.34 (m, 1H); 13C
NMR (CDCl3): d 134.2, 133.6, 132.2, 131.1, 130.1, 127.5, 126.7,
125.1, 124.2, 120.4, 120.1, 111.4, 98.9.
1 S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,
3451–3479.
2 M. C. Bryan, B. Dillon, L. G. Hamann, G. J. Hughes,
M. E. Kopach, E. A. Peterson, M. Pourashraf, I. Raheem,
P. Richardson, D. Richter and H. F. Sneddon, J. Med.
Chem., 2013, 56, 6007–6021.
(Z)-2-(2,4-Dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile
(14). Synthesised using the general procedure as described for
(3) from 1H-pyrrole-2-carbaldehyde (1) and 2,4-dichlor-
ophenylacetonitrile to afford 14 as a light yellow solid.
MP 148–156.6 ꢀC; IR n(cmꢂ1): 3381, 2208, 1593, 1141, 742,
594; 1H NMR (CDCl3): d 9.84 (brs, 1H), 7.47 (d, J ¼ 2.0 Hz, 1H),
7.36–7.27 (m, 2H), 7.16 (s, 1H), 7.12–7.08 (m, 1H), 6.71–6.66 (m,
1H), 6.39–6.33 (m, 1H). 13C NMR (CDCl3): d 137.65, 135.20,
133.81, 132.38, 131.34, 130.40, 127.86, 127.34, 124.86, 120.15,
119.98, 111.10, 97.68.
3 D. J. C. Constable, C. Jimenez-Gonzalez and
R. K. Henderson, Org. Process Res. Dev., 2007, 11, 133–137.
4 R. Gani, C. Jimenez-Gonzalez and D. J. C. Constable, Comput.
Chem. Eng., 2005, 29, 1661–1676.
5 K. Grodowska and A. Parczewski, Acta Pol. Pharm., 2010, 67,
3–12.
6 A. B. McGeachie, L. R. Odell, A. Quan, N. Chau, T. A. Hill,
D. J. Keating, M. A. Cousin, E. M. van Dam, J. Daniel,
A. Mariana, A. Whiting, S. Perera, A. Novelle, J. Gilbert,
J. A. Sakoff, M. Chircop, A. McCluskey and P. J. Robinson,
ACS Chem. Biol., 2013, 8, 1507–1518.
7 L. R. Odell, D. Howan, C. P. Gordon, M. J. Robertson,
N. Chau, A. Mariana, A. E. Whiting, R. Abagyan,
J. A. Daniel, N. N. Gorgani, P. J. Robinson and
A. McCluskey, J. Med. Chem., 2010, 53, 5267–5280.
8 C. P. Gordon, B. Venn-Brown, M. J. Robertson, K. A. Young,
N. Chau, A. Quan, P. J. Robinson and A. McCluskey, J. Med.
Chem., 2013, 56, 46–59.
(Z)-2-(4-Ethynylphenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (15).
Synthesised using the general procedure as described for (3)
from 1H-pyrrole-2-carbaldehyde (1) and 4-ethynylphenylaceto-
nitrile to afford 15 as a brown solid.
MP 100–102 ꢀC; IR n(cmꢂ1): 3446, 3268, 2194, 1588, 1037,
831, 720, 520, 435; 1H NMR (CDCl3): d 9.80 (brs, 1H), 7.60–7.47
(m, 4H), 7.41 (s, 1H), 7.12–7.05 (m, 1H), 6.75–6.68 (m, 1H), 6.40–
6.32 (m, 1H), 3.16 (s, 1H); 13C NMR (101 MHz, CDCl3): d 134.4,
19812 | RSC Adv., 2014, 4, 19806–19813
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9 M. Tarleton and A. McCluskey, Tetrahedron Lett., 2011, 52, 18 F. Freeman, Chem. Rev., 1980, 80, 329.
1583–1586.
19 L. F. Tietze, Chem. Rev., 1996, 96, 115.
10 C. P. Gordon, N. Byrne and A. McCluskey, Green Chem., 2010, 20 Y. O. Aharma and M. S. Degani, Green Chem., 2009, 11, 526.
12, 1000–1006.
21 K. Ebitani, K. Motokura, K. Mori, T. Mizugaki and
11 L. von Kleist, W. Stahlschmidt, H. Bulut, K. Gromova,
K. Kaneda, J. Org. Chem., 2006, 71, 5440.
D. Puchkov, M. J. Robertson, K. A. MacGregor, N. Tomlin, 22 E. Knoevenagel, Ber. Dtsch. Chem. Ges., 1896, 29, 172.
A. Pechstein, N. Chau, M. Chircop, J. A. Sakoff, J. von 23 L. F. Tietze, Pure Appl. Chem., 2004, 76, 1967.
¨
Kries, W. Saenger, H.-G. Krausslich, O. Shupliakov, 24 M. Tarleton, J. Gilbert, M. J. Robertson, A. McCluskey and
P. J. Robinson, A. McCluskey and V. Haucke, Cell, 2011,
146, 471–484.
12 C. B. Harper, M. R. Popoff, A. McCluskey, P. J. Robinson and
F. A. Meunier, Trends Cell Biol., 2013, 23, 90–101.
13 B. E. Campbell, M. Tarleton, C. P. Gordon, A. McCluskey,
J. A. Sakoff, MedChemComm, 2011, 2, 31–37.
25 M. Ali, J.-A. Bliese, M. Rasmussen, R. M. Sargent, S. Saubern,
D. G. Sawutz, J. S. Wilkie, D. A. Winkler, K. N. Winzenberg
and R. C. J. Woodgate, Bioorg. Med. Chem. Lett., 2007, 17,
993–997.
J. A. Sakoff, J. Gilbert and R. B. Gasser, Bioorg. Med. Chem. 26 G. Alberghina, M. E. Amato, F. A. Bottino, A. Corsaro and
Lett., 2011, 21, 3277–3281. S. Fisichella, J. Heterocycl. Chem., 1986, 23, 1747–1752.
14 M. J. Robertson, S. G. Stewart, C. P. Gordon, J. Gilbert, 27 W. Herz and J. Brasch, J. Org. Chem., 1958, 23, 711–714.
J. A. Sakoff and A. McCluskey, Bioorg. Med. Chem., 2011, 28 R. V. Hangarge, D. V. Jarikote and M. S. Shingare, Green
19, 5734–5741.
15 B. E. Campbell, A. Hoffman, A. McCluskey and R. B. Gasser, 29 P. Verdıa, F. Santamarta and E. Tojo, Molecules, 2011, 16,
Biotechnol. Adv., 2011, 29, 28–39. 4379–4388.
16 A. McCluskey, A. T. R. Sim and J. A. Sakoff, J. Med. Chem., 30 W. H. Correa, J. K. Edwards, A. McCluskey, I. McKinnon and
2002, 45, 1151–1175. J. L. Scott, Green Chem., 2003, 5, 30–33.
17 W. H. Correa, J. K. Edwards, A. McCluskey, I. McKinnon and 31 S. Zhao, X. Wang and L. Zhang, RSC Adv., 2013, 3, 11691–
Chem., 2002, 4, 266–268.
´
J. L. Scott, Green Chem., 2003, 5, 30–33.
11696.
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RSC Adv., 2014, 4, 19806–19813 | 19813