Investigation of the one-pot synthesis of quinolin-2-(1H)-ones and the discovery of a variation of the three-component Ugi reaction

Article abstract of DOI:10.1039/c0ob00029a

Rapid access to the quinolin-2-(1H)-one scaffold is afforded by a sequential 4 component Ugi-Knoevenagel condensation of an aminophenylketone, an aromatic aldehyde possessing electron donating moieties, cyanoacetic acid and an aliphatic isocyanide, in mod

Full text of DOI:10.1039/c0ob00029a

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PAPER
Investigation of the one-pot synthesis of quinolin-2-(1H)-ones and the
discovery of a variation of the three-component Ugi reaction†
Christopher P. Gordon, Kelly A. Young, Lacey Hizartzidis, Fiona M. Deane and Adam McCluskey*
Received 22nd April 2010, Accepted 9th November 2010
DOI: 10.1039/c0ob00029a
Rapid access to the quinolin-2-(1H)-one scaffold is afforded by a sequential 4 component
Ugi–Knoevenagel condensation of an aminophenylketone, an aromatic aldehyde possessing electron
donating moieties, cyanoacetic acid and an aliphatic isocyanide, in moderate to good yields (49–71%).
Interestingly, when the reaction is performed using aromatic aldehydes bearing electron withdrawing
moieties or isocyanides containing aromatic or ester units, a mixture of a quinolin-2-(1H)-one and an
a-amino amide (Ugi three-component adduct) is afforded in varying ratios. Further when the reaction
is performed utilizing a combination of an isocyanide-containing aromatic or carbonyl unit, and an
aldehyde possessing an electron withdrawing functionality, the Ugi three-component adduct is
exclusively afforded. In our hands this new variation of the Ugi 3CR proved to be efficient and robust
affording analogues in good yields (51–70%).
The pivotal reaction affording the dynoles (1), Bis-T’s (2), and
iminodyns (3) is the Knoevenagel condensation which in our hands
The success of a medicinal chemistry program is inexorably linked
(and those of others) has continually proven to be a high yielding
Introduction
and extremely robust reaction.2–21 Similarly the Ugi 4-component
reaction (Ugi 4CR), utilized to access the isoindole-3-carboxamide
scaffold (4),6,7,22–27 has proven a high yielding reaction tolerating
a diverse range of functional groups. Consequently in our efforts
to unearth additional series’ of biologically active scaffolds our
attention was drawn to a series of quinolin-2-(1H)-ones (5).28
Entry to the quinolin-2-(1H)-ones scaffold could be afforded
via a one-pot sequential Ugi 4CR followed by spontaneous
intramolecular Knoevenagel cyclisation. The reaction entails
treating an aminophenyl ketone (6) with an aromatic aldehyde (7),
followed by addition of cyanoacetic acid (8), and an isocyanide
(9) to form the corresponding Ugi product (10) which undergoes
spontaneous intramolecular Knoevenagel condensation between
the cyanoacetic acid moiety and the carbonyl derived from the
aminophenyl ketone (Scheme 1).
to developing and utilizing synthetically accessible scaffolds that
are amenable to diverse functional group alterations. To this
end we place synthetic elegance over complexity focusing on
high yielding and multi-component chemistry to drive diversity-
oriented synthesis.1 This ethos has afforded our team a suite of
biologically active scaffolds including the dynoles (1),2 Bis-Ts (2),3,4
and iminodyns (3),5 which are potent dynamin GTPase inhibitors,
and the isoindole-3-carboxamide (4) scaffold which has displayed
promising cytotoxicity activity against a panel of human cancer
cell lines (Fig. 1).6,7
Fig. 1 Generic structures of the dynole (1), Bis-T (2), iminodyn (3), and
isoindole-3-carboxamide (4) scaffolds.
Scheme 1 Reagents and conditions: (i) MeOH, rt; (ii) spontaneous.
Chemistry, School of Environmental & Life Sciences, The University of
Newcastle, University Drive, Callaghan, NSW 2308, Australia. E-mail:
Adam.McCluskey@newcastle.edu.au; Fax: 61 2492 15472; Tel: 61 2492
16486
Following the reported synthetic route we examined a num-
ber of aromatic aldehydes, two aminophenylketones (2-amino-
benzophenone and 1-(2-aminophenyl)ethanone), and a number
of aliphatic isocyanides. Typically these reactions proceeded
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra. See DOI: 10.1039/c0ob00029a
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Table 1 Isolated yields of quinolin-2-(1H)-ones (11–17) arising from the
4-component Ugi-Knoevenagel reaction
Entry (compound)
R1
Ar
R2
Yield (%)
56
1 (11)
2 (12)
3 (13)
4 (14)
5 (15)
6 (16)
7 (17)
68
71
66
49
68
49
Scheme 2 Reagents and conditions; (i) MeOH, rt, 24 h.
As with our initial investigations, moderate to good (combined)
yields (58–74%) were observed (Table 2), but now we note the
presence of both the Ugi 4CR and Ugi 3CR products. Entries
1–5 (Table 2) indicate the presence of Ugi 4CR and Ugi 3CR
in varying ratios, with the Ugi 4CR product being the major
product isolated in entries 2–4, and the Ugi 3CR in entries 1
and 5. Interestingly with entries 6 and 7, the Ugi 3CR product
is the sole reaction product. Thus a trend was emerging, with
reactions utilizing aldehydes bearing electron donating moieties
favouring the formation of the Ugi 4CR, whilst utilization of
electron withdrawing aldehydes favoured the Ugi 3CR outcome.
However the reaction drivers are more complex with the isocyanide
moiety also important in governing the reaction outcome with the
introduction of an ester moiety (Table 2 entry 3) resulting in a
change in product distribution from 1 : 2.7 (Ugi 3CR : Ugi 4CR;
Table 2 entry 2) to 1 : 1.1 (Ugi 3CR : Ugi 4CR; Table 2 entry 3). The
ester isocyanide reaction also affords a higher (combined) yield
at 72% versus 49%. The best yield obtained in this series is 74%
(Table 2, entry 7), and this reaction utilized the sterically bulky 2,6-
dimethylphenyl isocyanide, suggesting that an isocyanide bearing
a bulky aromatic andester moiety may favour the Ugi3CR product
over the Ugi 4CR product.
smoothly in moderate to good isolated yields (49–71%,
Table 1).19
The Ugi–Knoevenagel reaction tolerates a range of differing
aldehydes, with electron donating aldehydes affording higher
isolated yields (Table 1, entries 2–4 and 6). Electron withdrawing
aldehydes (Table 1, entries 1 and 7) appear to provide lower
yields of the Ugi–Knoevenagel product. We also investigated the
synthesis of 13 in CH2Cl2 and THF, and in both instances noted
a significant reduction in product yield isolating 52% and 43%,
respectively. This suggests, that of the solvent systems examined,
CH3OH is the favoured system for this transformation. Of the
Table 1 entries, entry 5 is the sole example utilizing a functionalised
isocyanide, and it too affords a low yield of the Ugi–Knoevenagel
product, even in the presence of 4-methoxybenzaldehyde, which
afforded a good yield with simple isocyanides (Table 1, entries
2 and 6). As such we thought that the increased functionality
afforded by the ester moiety might be responsible for the reduced
yield observed. Accordingly we examined this reaction with the
related ethyl isocyanopropionate (18) (Scheme 2).
In this instance we observed two distinct products by TLC. Sub-
sequent isolation via silica gel flash chromatography and charac-
terization revealed that the higher Rf compound was an a-amino
amide, 21a, an Ugi three-component (Ugi 3CR) adduct, whereas
the lower Rf compound was the anticipated Ugi–Knoevenagel
adduct, 21b in a 58% combined yield. The isolation of an Ugi
3CR product as the major component of this reaction mixture
was unexpected, and as far as we are aware, not known for systems
such as these. This observation warranted further examination. An
additional series of reactions investigating a number of aliphatic, a
hindered aromatic, and two ester containing isocyanides (Table 2)
was thus conducted.
To further evaluate the influence of the isocyanide moiety
we examined an additional series of reactions utilising the
bulky aromatic isocyanides 2,6-dimethylphenyl isocyanide and 2-
isocyanonaphthalene (Table 3).
In all instances, the reactions utilizing either 2,6-dimethylphenyl
isocyanide or 2-isocyanonaphthalene afforded only the Ugi 3CR
products in moderate to good yields (Table 3, 51–70%). Also
of note here is that the presence of electron donating aldehydes
(Table 3, entries 2 and 5) and electron withdrawing aromatic
aldehydes (Table 3, entries 1, 3 and 4) do not effect the Ugi 3CR
outcome. This suggests that the nature of the isocyanide is of
far greater importance in governing the reaction outcome. The
reaction proceeded well with both 2-aminobenzophenone and 1-
(2-aminophenyl)ethanone, also affording the Ugi 3CR outcome.
The Ugi 3CR reaction has been reported on a handful
of occasions,26–30 but until now has required the addition of
29
B(OMe)3 or catalytic quantities of exotic organic acids such
as phenylphosphonic and phenylphosphinic acid.26–30 However,
this variant of the reaction was conducted in the absence of an
added catalyst. Given the different reaction outcomes via the
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Table 2 Isolated yields of a-amino amides (21a–25a, 26 and 27) and quinolin-2-(1H)-ones (21b–25b) arising from the attempted Ugi–Knoevenagel
condensation reaction
Entry (compound)
R1
Ar
R2
Yield% (a)
33
Yield% (b)
25
a : b
1 (21a and 21b)
1.3 : 1
2 (22a and 22b)
3 (23a and 23b)
4 (24a and 24b)
16
35
31
43
37
38
1 : 2.7
1 : 1.1
1 : 1.2
5 (25a and 25b)
6 (26)
42
58
74
26
0
1.1 : 1
—
7 (27)
0
—
Table 3 Isolated yields of a-amino amides (28–32) arising from the Ugi
a methanolic solution of 4-nitrobenzaldehyde (33) was treated
with 1-(2-aminophenyl)ethanone (34), ethyl isocyanopropionate
(35) and a stoichiometric amount of cyanoacetic acid (8), which
afforded the Ugi 3CR adduct 36 (Scheme 3) in a 58% yield. The
reaction was subsequently attempted with a catalytic amount,
and in the absence of cyanoacetic acid, respectively, and in both
cases only starting materials were returned, clearly demonstrating
that cyanoacetic acid plays a crucial role and is required in
stoichiometric quantities for the Ugi 3CR.
3CR using bulky aromatic isocyanides
Entry (compound)
R1
Ar
R2
Yield% (a)
54
1 (28)
2 (29)
3 (30)
69
51
4 (31)
5 (32)
51
70
Scheme 3 Reagents and conditions; (i) MeOH, 24 h, rt.
It was postulated that the ‘malonic-like’ methylene carbon of
cyanoacetic acid may be influencing the reaction, possibly acting
via a similar mechanism to that proposed for phenyl phosphinic
acid.15 To investigate this inference the reaction was repeated
replacing cyanoacetic acid with methyl cyanoacetate (37) and,
as outlined in Scheme 4, this reaction exclusively afforded the
Knoevenagel adduct 38. Thus it was apparent that the ‘malonic-
like’ methylene carbon of the cyanoacetic acid was unlikely to
Ugi 3CR and Ugi 4CR, it is logical that the cyanoacetic acid
had two distinct roles in this series of Ugi 3/4CRs. Accordingly
a series of reactions were conducted in a bid to elucidate
the role of cyanoacetic acid in this new variation of the Ugi
3CR. Initially we conducted a point of reference reaction whereby
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Scheme 4 Reagents and conditions; (i) MeOH, 24 h, rt.
be influencing the reaction, rather the carboxylic acid proton is
pivotal to this variant of the Ugi 3CR.
However, as yet it was not clear if a simple carboxylic acid,
rather than cyanoacetic acid, would also facilitate access to the
Ugi 3CR. Accordingly, four additional reactions were performed
using 2-butynoic acid (39), 2-butenoic acid (40), 2-methoxyacetic
acid (41) and 3,3,3-trifluoropropionic acid (42) (Scheme 5). In
these reactions no product was isolated with 2-methyoxyacetic
acid, and only the Ugi 4CR adducts were observed in 60% (43),
66% (44) and 50% (45) yields, respectively, thus emphasizing the
importance of cyanoacetic acid to this Ugi 3CR.
Fig. 2 Partial proposed mechanism for the Ugi 4CR and 3CR reactions.
We believed that this new variation of the Ugi 3CR was
controlled by two factors, firstly the reduced nucleophilicity of
cyanoacetic acid resulting from the electron withdrawing effect
of the nitrile moiety, and secondly the stability of the nitrilium
ion. Thus it was anticipated that as the stability of the nitrilium
ion increased the ability of the cyanoacetic acid anion, a poor
nucleophile, to react with the nitrilium intermediate would be
reduced. This would allow water to act as the internal nucleophile
and favour the formation of the Ugi 3CR over the Ugi 4CR.
In summary, we have unearthed a new variation of the Ugi
3CR. Evidence indicates that the reaction is promoted by the
reduced nucleophilicity of the cyanoacetic acid anion. In our hands
this new variation of the Ugi 3CR proved to be efficient and robust
affording analogues in good yields with little to no purification
required. Further studies in our laboratory are underway to
investigate a range of electron deficient carboxylic acids and will
be reported in due course.
Scheme 5 Reagents and conditions; (i) MeOH, 24 h, rt.
Mechanistically both the Ugi 3CR and 4CR are believed to
proceed via a nitrilium ion intermediate (46) which results from
the addition of the isocyanide to an in situ generated iminium
ion (47).18,31–33 To afford the Ugi 4CR product it is proposed the
carboxylate ion adds to the nitrilium ion via nucleophilic addition
whereas during the Ugi 3CR it is proposed that water, generated
during the initial imine formation, acts as the internal nucleophile
(Fig. 2).28
Experimental section
All reagents were purchased from Sigma-Aldrich, Matrix Scientific
or Lancaster Synthesis and were used without purification. With
the exception of THF (anhydrous > 99%) obtained from Sigma–
Aldrich, all solvents were re-distilled from glass prior to use.
1H and 13C NMR spectra were recorded on a Bruker AvanceTM
AMX 300 MHz spectrometer at 300.1315 and 75.4762 MHz,
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respectively. Chemical shifts (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.
Melting points were recorded on a Stuart Scientific melting
point apparatus (UK) and are uncorrected. Thin layer chro-
matography (TLC) was performed on Merck silica gel 60 F254
pre-coated aluminium plates with a thickness of 0.2 mm. Column
chromatography was performed under ‘flash’ conditions on Merck
silica gel 60 (230–400 mesh) or using the Biotage SP4 flash
purification system with a 100 g pre-packed snap column.
2-(3-Cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(4-
hydroxyphenyl)-N-(pentan-2-yl)acetamide (13)
Synthesized utilizing the general procedure described above,
from 2-aminobenzophenone (0.52 g, 2.63 mmol), 4-hydroxy-
benzaldehyde (0.32 g, 2.63 mmol), cyanoacetic acid (0.23 g,
2.63 mmol) and 2-pentylisocyanide (0.32 mL, 2.63 mmol) in
MeOH (5.0 mL) to afford 13 (0.87 g, 71%) as a yellow solid (mp
203–205 ◦C). IR (KBr) 3407 (NH), 3245 (OH), 3057 (CH), 2961,
2930, 2871 (CH), 2231 (CN), 1665, 1650 (CO), 1605 (CC), 1517
(NH), 757 (CH) cm-1. 1H NMR (300 MHz) (DMSO-d6) d 9.53 (1
H, bs), 7.82 (1 H, d, J = 6.7 Hz), 7.75–7.40 (6 H, m), 7.28–7.13
(3 H, m), 6.99 (1 H, bs), 6.97 (1 H, d, J = 7.3 Hz), 6.74 (2 H,
d, J = 8.3 Hz), 3.87, 3.63 (1 H, m, d.r. 3 : 1), 1.60–1.13 (4 H, m),
1.09, 0.89 (3 H, d, J = 6.5 Hz, d.r. 1 : 3), 0.69, 0.57 (3 H, t, J =
7.2 Hz, d.r. 3 : 1); 13C NMR (75 MHz) (DMSO-d6) d 166.6, 166.1,
159.5, 159.4, 158.8, 156.7, 139.8, 133.6, 132.7, 129.9, 129.4, 129.3,
128.8, 128.6, 124.8, 124.6, 123.0, 119.5, 118.1, 115.4, 115.0, 105.8,
59.4, 52.3, 44.8, 44.6, 37.8, 37.5, 30.6, 26.7, 26.2, 20.6, 20.2, 19.0,
18.4, 13.7, 13.6, 10.6, 9.9; MS (ESI-) m/z 464 (M-1, 50%); HRMS
(ESI-) for C29H26N3O3, calculated 464.2052 found 464.2052.
General procedure
2-(4-Chlorophenyl)-2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-
yl)-N-((trimethylsilyl)methyl)acetamide (11).
A
solution of
MeOH (5.0 mL), 2-aminobenzophenone (0.60 g, 3.00 mmol)
and 4-chlorobenzaldehye (0.42 g, 3.00 mmol) was stirred at
room temperature for 0.5 h. To the stirred solution was added
cyanoacetic acid (0.25 g, 3.00 mmol) followed by the addition
of (trimethylsilyl)methyl isocyanide (0.42 mL, 3.00 mmol). The
reaction mixture was stirred at room temperature for 24 h and
the resulting precipitate was collected, washed with diethyl ether,
and dried to afford 11 (0.84 g, 56%) as a yellow solid (mp 168–
170 ◦C). IR (KBr) 3435 (NH), 3057 (CH), 2951, 2856 (CH), 2229
(CN), 1654 (CO), 1604 (CC), 1552 (NH), 858 (SiC), 758 (CH), 700
(CCl) cm-1. 1H NMR (300 MHz) (CDCl3) d 7.74–7.62 (4 H, m),
7.62–7.55 (3 H, m), 7.54–7.47 (2 H, m), 7.41 (4 H, s), 7.28–7.20
(1 H, m), 7.02 (1 H, bs), 6.25 (1 H, bs), 2.84 (2 H, AB q, J =
23.4, 5.8 Hz), 0.03 (9 H, s); 13C NMR (75 MHz) (CDCl3) d 169.3,
163.3, 162.2, 142.4, 136.8, 136.2, 136.0, 134.9, 132.9, 132.5, 131.9,
131.7, 131.6, 131.6, 131.4, 126.3, 122.9, 120.5, 117.3, 108.8, 62.9,
33.1, 0.01; MS (ESI-) m/z 498 (M-1, 100%); HRMS (ESI-) for
C28H25ClN3O2Si, calculated 498.1483, found 498.1483.
2-(3-Cyano-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-hydroxy-
phenyl)-N-(pentan-2-yl)acetamide (14). Synthesized utilizing
the general procedure described above, from 1-(2-amino-
phenyl)ethanone (0.59 g, 4.30 mmol), 4-hydroxybenzaldehyde
(0.53 g, 4.30 mmol), cyanoacetic acid (0.37 g, 4.30 mmol) and
2-pentylisocyanide (0.52 mL, 4.30 mmol) in MeOH (5.0 mL) to
afford 14 (1.14 g, 66%) as a white solid (mp 198–199 ◦C). IR (KBr)
3367 (NH), 3232 (OH), 3057 (CH), 2962, 2931, 2872 (CH), 2230
(CN), 1664, 1640 (CO), 1611 (CC), 1512 (NH), 753 (CH) cm-1. 1H
NMR (300 MHz) (DMSO-d6) d 9.43 (1 H, s), 7.95 (1 H, d, J = 8.1
Hz), 7.74 (1 H, d, J = 8.1 Hz), 7.57–7.47 (1 H, m), 7.44–7.33 (1 H,
m), 7.29 (1 H, t, J = 7.6 Hz), 7.07 (2 H, dd, J = 8.5, 2.1 Hz), 6.94–
6.86 (1 H, m), 6.69 (2 H, d, J = 8.5 Hz), 3.92–3.75, 3.68–3.52 (1 H,
m, d.r. 3 : 1), 2.77 (3 H, s), 1.50–1.12 (4 H, m), 1.08–1.02, 0.91–0.80
(3 H, m, d.r. 1 : 3), 0.67, 0.51 (3 H, t, J = 7.3 Hz, d.r. 3 : 1); 13C NMR
(75 MHz) (DMSO-d6) d 166.7, 166.1, 158.7, 157.7, 157.7, 156.6,
139.0, 132.6, 129.3, 129.2, 127.0, 124.8, 124.8, 124.7, 122.9, 119.6,
117.9, 115.6, 114.9, 105.8, 59.0, 58.8, 52.2, 44.7, 44.5, 37.8, 37.5,
30.6, 26.7, 26.2, 20.5, 20.2, 19.0, 18.3, 18.3, 13.7, 13.6, 10.6, 10.0;
MS (ESI-) m/z 402 (M-1, 60%); HRMS (ESI-) for C24H24N3O3,
calculated 402.1896 found 402.1895.
2-(3-Cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(4-methoxy-
phenyl)-N-(pentan-2-yl)acetamide (12). Synthesized utilizing the
general procedure described above, from 2-aminobenzophenone
(0.52 g, 2.70 mmol), 4-methoxybenzaldehyde (0.32 mL,
2.70 mmol), cyanoacetic acid (0.23 g, 2.70 mmol) and 2-pentyliso-
cyanide (0.32 mL, 2.70 mmol) in MeOH (5.0 mL) to afford 12
(0.88 g, 68%) as a yellow solid (158–159 ◦C). IR (KBr) 3336 (NH),
3058 (CH), 2953, 2929, 2870 (CH), 2837 (CH), 2228 (CN), 1652
(CO), 1604 (CC), 1512 (NH), 1249 (CO), 757 (CH) cm-1. 1H NMR
(300 MHz) (Acetone-d6) d 7.68–7.61 (3 H, m), 7.60–7.49 (3 H, m),
7.46 (1 H, dd, J = 8.2, 0.6 Hz), 7.47–7.39 (2 H, m), 7.37–7.31 (1
H, m), 7.26–7.18 (1 H, m), 7.12–7.07 (1 H, m), 7.01 (1 H, bs),
7.05–6.98 (1 H, m), 6.94–6.88 (2 H, m), 4.12–3.93 (1 H, m), 3.77
(3 H, s), 3.35 (3H, s), 1.60–1.25 (3 H, m), 1.06, 0.89 (1 H, d, J =
6.6 Hz, dr 1 : 3), 0.95–0.84 (2 H, m), 0.74, 0.66 (3 H, t, J = 7.3 Hz,
dr 3 : 1); 13C NMR (75 MHz) (Acetone-d6) d 165.9, 165.8, 159.4,
158.8, 158.6, 139.7, 133.7, 132.4, 129.4, 129.3, 129.2, 128.8, 128.6,
128.3, 128.3, 128.2, 128.1, 125.9, 125.8, 122.6, 119.6, 117.5, 117.4,
114.3, 113.3, 59.6, 59.5, 54.2, 52.3, 44.9, 44.8, 37.8, 37.5, 26.5,
26.1, 19.7, 19.4, 18.7, 18.2, 12.8, 12.7, 9.6, 9.1; MS (ESI+) m/z 480
(M+1, 100%); HRMS (ESI+) for C30H30N3O3, calculated 480.2209
found 480.2207.
Methyl 2-(2-(3-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-
methoxyphenyl)acetamido)acetate (15). Synthesized utilizing
the general procedure described above, from 1-(2-amino-
phenyl)ethanone (0.80 mL, 6.54 mmol), 4-methoxybenzaldehyde
(0.89 g, 6.54 mmol), cyanoacetic acid (0.56 g, 6.54 mmol) and
methylisocyanoacetate (0.80 mL, 6.54 mmol) in MeOH (5.0 mL)
to afford 15 (1.34 g, 49%) as a light brown solid (mp 245–246
◦C). IR (KBr) 3367 (NH), 2985, 2951 (CH), 2844 (CH), 2228
(CN), 1742 (COO), 1675, 1656 (CO), 1609 (CC), 1512 (NH),
1
1246 (CO), 754 (CH) cm-1. H NMR (300 MHz) (DMSO-d6) d
8.49 (1 H, t, J = 5.0 Hz), 7.96 (1 H, d, J = 8.1 Hz), 7.55 (1 H, t,
J = 7.6), 7.45–7.26 (4 H, m), 7.10 (1 H, bs), 6.88 (2 H, d, J = 8.7
Hz), 3.92–3.76 (2 H, m), 3.70 (3 H, s), 3.61 (3 H, s), 2.77 (3 H,
s); 13C NMR (75 MHz) (DMSO-d6) d 169.9, 167.5, 158.7, 158.6,
158.0, 138.7, 132.8, 129.5, 128.0, 127.2, 126.0, 123.0, 119.7, 117.8,
115.5, 113.9, 113.7, 105.6, 58.3, 55.0, 51.6, 41.1, 18.3; MS (ESI-)
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m/z 418 (M-1, 100%); HRMS (ESI-) for C23H20N3O5, calculated
418.1481 found 418.1481.
133.7, 130.8, 128.7, 127.9, 127.6, 118.3, 115.4, 111.9, 61.6, 60.1,
34.6, 33.1, 28.7, 13.5; MS (ESI+) m/z 465 (M+1, 100%); HRMS
(ESI+) for C26H25ClN2O4, calculated 464.1503 found 464.1504.
Further elution (4 : 1 hexanes–EtOAc) afforded 21b (0.38 g,
25%) as a yellow oil. IR (film) 3346 (NH), 3058 (CH), 2980,
2937 (CH), 2230 (CN), 1730 (COO), 1657 (CO), 1605 (CC), 1554
(NH), 1254 (CO), 760 (CH), 703 (CCl) cm-1. 1H NMR (300 MHz)
(CDCl3) d 7.54–7.44 (3 H, m), 7.43–7.27 (7 H, m), 7.21 (1 H, s),
7.12–6.96 (2 H, m), 6.85 (1 H, bs), 4.01–3.86 (2 H, m), 3.48–3.34 (2
H, m), 2.47–2.32 (2 H, m), 1.09 (1 H, t, J = 7.1 Hz); 13C NMR (75
MHz) (CDCl3) d 171.3, 166.5, 160.0, 158.8, 139.2, 133.7, 133.1,
132.8, 131.4, 129.7, 129.4, 129.1, 128.4, 128.1, 123.1, 119.6, 116.5,
114.2, 105.6, 60.0, 59.9, 35.1, 32.9, 30.3, 28.7, 13.5; MS (ESI-) m/z
512 (M-1, 100%); HRMS (ESI-) for C29H24ClN3O4, calculated
513.1455 found 513.1455.
2-(3-Cyano-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-methoxy-
phenyl)-N-(2,4,4-trimethylpentan-2-yl)acetamide (16). Synthe-
sized utilizing the general procedure described above, from
1-(2-aminophenyl)ethanone (0.52 g, 3.80 mmol), 4-methoxy-
benzaldehyde (0.50 mL, 3.80 mmol), cyanoacetic acid (0.33 g,
3.80 mmol) and 1,1,3,3-tetramethylbutylisocyanide (0.70 mL,
3.80 mmol) in MeOH (5.0 mL) to afford 16 (1.18 g, 68%) as a
white solid (mp 187–188 ◦C). IR (KBr) 3430 (NH), 2953, 2909
(CH), 2839 (CH), 2227 (CN), 1684, 1659 (CO), 1607 (CC), 1514
(NH), 1246 (CO), 755 (CH) cm-1. 1H NMR (300 MHz) (DMSO-
d6) d 7.94 (1 H, d, J = 8.0 Hz), 7.57–7.40 (2 H, m), 7.35 (1 H,
bs), 7.32–7.24 (1 H, m), 7.18 (2 H, d, J = 8.4 Hz), 6.94–6.84 (3
H, m), 3.70 (3 H, s), 2.76 (3 H, s), 1.73–1.54 (2 H, m), 1.29 (6 H,
d, J = 11.0 Hz), 0.85 (9 H, s); 13C NMR (75 MHz) (DMSO-d6) d
165.7, 158.6, 158.4, 157.7, 139.1, 132.4, 129.0, 126.9, 122.8, 119.5,
118.1, 115.5, 113.7, 105.6, 60.0, 55.0, 54.7, 50.9, 31.1, 30.9, 28.5,
28.4, 18.2; MS (ESI-) m/z 458 (M-1, 100%); HRMS (ESI-) for
C28H32N3O3, calculated 458.2522 found 458.2522.
2-(2-Benzoylphenylamino)-N-cyclohexyl-2-(4-methoxyphenyl)-
acetamide (22a) and 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-
yl)-N-cyclohexyl-2-(4-methoxyphenyl)acetamide (22b). Synthe-
sized utilizing the general procedure, described above, from
2-aminobenzophenone (0.02 g, 1.00 mmol), 4-methoxy-
benzaldehyde (0.12 mL, 1.00 mmol), cyanoacetic acid (0.09 g,
1.00 mmol) and cyclohexylisocyanide (0.12 mL, 1.00 mmol) in
MeOH (5.0 mL). The crude material was subjected to flash silica
gel column chromatography (4 : 1 hexanes–EtOAc) to afford 22a
(0.07 g, 16%) as a yellow oil. IR (film) 3305 (NH), 3070 (CH), 2929,
2857 (CH), 1650 (CO), 1507 (NH), 1250 (CO), 749 (CH) cm-1. 1H
NMR (300 MHz) (CDCl3) d 9.14 (1 H, d, J = 4.1 Hz), 7.62 (2
H, d, J = 8.0 Hz), 7.44 (3 H, m), 7.33 (1 H, t, J = 5.2 Hz), 7.29
(2 H, d, J = 7.4 Hz), 6.64 (1 H, d, J = 7.6 Hz), 6.59 (2 H, d, J =
8.5 Hz), 4.94 (1 H, d, J = 4.1 Hz), 3.86 (1H, m), 3.83 (3H, s),
2.02–1.80 (5H, m), 1.68 (2H, m), 1.50–1.27 (4H, m), 1.11 (2H, m);
13C NMR (75 MHz) (CDCl3) d 199.0, 169.6, 159.1, 149.4, 139.3,
134.7, 134.5, 130.8, 129.5, 128.7, 128.4, 127.8, 132.6, 118.2, 115.5,
114.0, 113.6, 112.4, 62.56, 54.75, 47.6, 32.3, 24.2, 24.1; MS (ESI+)
m/z 443 (M+1, 100%); HRMS (ESI+) for C28H30N2O3, calculated
442.2256 found 442.2256.
Further elution (4 : 1 hexanes–EtOAc) afforded 22b (0.21 g,
43%) as a yellow crystalline solid (mp 174–175 ◦C). IR (KBr)
3341 (NH), 3058 (CH), 2929, 2852 (CH), 2228 (CN), 1654 (CO),
1605 (CC), 1512 (NH), 1250 (CO), 757 (CH) cm-1. 1H NMR (300
MHz) (CDCl3) d 7.60–7.52 (3 H, m), 7.52–7.50 (2 H, m), 7.50–
7.40 (2 H, m), 7.40–7.33 (3 H, m), 7.18–7.06 (1 H, m), 6.89 (2
H, d, J = 8.6 Hz), 6.64 (1H, bs), 5.97 (1 H, d, J = 4.1 Hz), 3.78
(3H, s), 2.07–1.91 (1H, m), 1.83–1.52 (5H, m), 1.37–1.25 (2H, m),
1.19–1.00 (3H, m); 13C NMR (75 MHz) (CDCl3) d 166.6, 160.4,
159.8, 159.6, 140.5, 133.7, 133.5, 130.3, 129.9, 129.8, 129.1, 128.9,
125.9, 123.4, 120.3, 117.2, 114.9, 114.7, 114.1, 106.7, 62.0, 55.5,
53.9, 49.0, 32.8, 32.8, 31.9, 29.4, 25.6, 24.9; MS (ESI-) m/z 490
(M-1, 100%); HRMS (ESI-) for C31H28N3O3, calculated 490.2209
found 490.2209.
2-(3-Cyano-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-nitrophenyl)-
N-(2,4,4-trimethylpentan-2-yl)acetamide
(17). Synthesized
utilizing the general procedure described above, from 1,1-(2-
aminophenyl)ethanone (0.60 g, 4.40 mmol), 4-nitrobenzaldehyde
(0.67 g, 4.40 mmol), cyanoacetic acid (0.38 g, 4.40 mmol) and
1,1,3,3-tetramethylbutylisocyanide (0.80 mL, 4.40 mmol) in
MeOH (5.0 mL) to afford 17 (1.02 g, 49%) as a yellow solid (mp
167–168 ◦C). IR (KBr) 3325 (NH), 3058 (CH), 2957, 2946 (CH),
2225 (CN), 1681, 1633 (CO), 1608 (CC), 1558 (NO2), 1514 (NH),
1346 (NO2), 756 (CH) cm-1. 1H NMR (300 MHz) (DMSO-d6) d
8.16 (2 H, d, J = 8.7 Hz), 8.00 (1 H, dd, J = 8.0, 1.6 Hz), 7.65 (1 H,
s), 7.54 (1 H, t, J = 7.4, 7.4 Hz), 7.45 (2 H, d, J = 8.7 Hz), 7.33 (1
H, t, J = 7.6 Hz), 7.27 (1 H, d, J = 8.6 Hz), 6.95 (1 H, s), 2.79 (3 H,
s), 1.71 (1 H, d, J = 14.6 Hz), 1.52 (1 H, d, J = 14.6 Hz), 1.24 (6 H,
d, J = 4.2 Hz), 0.82 (9 H, s); 13C NMR (75 MHz) (DMSO-d6) d
164.6, 158.6, 158.1, 152.7, 146.6, 142.5, 138.8, 132.9, 131.6, 130.5,
129.2, 127.3, 124.1, 124.0, 123.2, 123.1, 119.7, 117.4, 115.4, 105.8,
59.9, 55.0, 50.7, 31.1, 30.7, 28.7, 28.0, 18.3; MS (ESI-) m/z 473
(M-1, 100%); HRMS (ESI-) for C27H29N4O4, calculated 473.2267
found 473.2267.
Ethyl-3-(2-(2-benzoylphenylamino)-2-(4-chlorophenyl)acetami-
do)propanoate (21a) and ethyl-3-(2-(4-chlorophenyl)-2-(3-cyano-
2-oxo-4-phenylquinolin-1(2H)-yl)acetamido)propanoate
(21b).
Synthesized utilizing the general procedure described above, from
2-aminobenzophenone (0.60 g, 3.00 mmol), 4-chlorobenzaldehyde
(0.42 g, 3.00 mmol), cyanoacetic acid (0.25 g, 3.00 mmol) and ethyl
isocyanopropionate (0.4 mL, 3.00 mmol) in MeOH (5.0 mL). The
crude reaction mixture was subjected to flash silica gel column
chromatography (4 : 1 hexanes–EtOAc) to afford 21a (0.46 g,
33%) as a yellow oil. IR (film) 3331 (NH), 3077 (CH), 2978 (CH),
2225 (CN), 1732 (COO), 1660, 1624 (CO), 1563, 1511 (NH), 1254
(CO), 753 (CH), 701 (CCl) cm-1. 1H NMR (300 MHz) (CDCl3) d
9.14 (1 H, d, J = 4.1 Hz), 7.62 (2 H, d, J = 8.0 Hz), 7.53–7.36 (6
H, m), 7.34–7.26 (4 H, m), 6.59 (2 H, d, J = 8.5 Hz), 4.94 (1 H, d,
J = 4.1 Hz), 3.94 (2 H, q, J = 6.6 Hz), 3.49–3.42 (2 H, m), 2.42 (2
H, t, J = 5.9 Hz), 1.12 (3 H, t, J = 6.9 Hz); 13C NMR (75 MHz)
(CDCl3) d 199.0, 171.4, 170.0, 148.9, 139.2, 136.0, 134.8, 134.4,
Methyl-2-(2-(2-benzoylphenylamino)-2-(4-methoxyphenyl)acet-
amido)acetate
(23a)
and
methyl-2-(2-(3-cyano-2-oxo-4-
phenylquinolin-1(2H)-yl)-2-(4-methoxyphenyl)acetamido)acetate
(23b). Synthesized utilizing the general procedure, described
above, from 2-aminobenzophenone (0.20 g, 1.00 mmol),
4-methoxybenzaldehyde (0.12 mL, 1.00 mmol), cyanoacetic
acid (0.09 g, 1.00 mmol) and methylisocyanoacetate (0.10 mL,
1.00 mmol) in MeOH (5.0 mL). The crude reaction material
1424 | Org. Biomol. Chem., 2011, 9, 1419–1428
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was subjected to flash silica gel column chromatography (1 : 1
hexanes–EtOAc) to afford 23a (0.17 g, 35%) as a yellow oil. IR
(film) 3311 (NH), 3064 (CH), 2952, 2837 (CH), 1753 (COO), 1664,
1623 (CO), 1510 (NH), 1252 (CO), 1178 (CO), 753 (CH) cm-1. 1H
NMR (300 MHz) (Acetone-d6) d 7.64–7.42 (8 H, m), 7.38–7.30
(1 H, m), 6.93 (2 H, d, J = 8.8 Hz), 6.76 (1 H, d, J = 8.6 Hz),
6.64–6.56 (1 H, m), 5.27 (1 H, s), 4.02 (1 H, dd, J = 17.5, 1.0 Hz),
3.90 (1 H, dd, J = 17.6, 1.0 Hz), 3.77 (3 H, s), 3.62 (3 H, s); 13C
NMR (75 MHz) (Acetone-d6) d 199.4, 171.8, 170.7, 160.5, 150.4,
141.2, 135.7, 135.5, 131.9, 131.7, 129.9, 129.5, 129.0, 119.1, 115.7,
115.0, 113.8, 61.3, 55.6, 52.2, 41.6; MS (ESI+) m/z 433 (M+1,
100%); HRMS (ESI+) for C25H25N2O5, calculated 433.1685 found
433.1687.
Further elution (1 : 1 hexanes–EtOAc) afforded 23b (0.18 g,
37%) as a yellow oil. IR (film) 3406 (NH), 2969, 2834 (CH), 2229
(CN), 1750 (COO), 1686 (CO), 1653 (CO), 1606 (CC), 1514 (NH),
1251, 1181 (CO), 758 (CH) cm-1. 1H NMR (300 MHz) (Acetone-
d6) d 7.70–7.60 (5 H, m), 7.60–7.47 (5 H, m), 7.34 (1 H, dd, J =
8.1, 1.2 Hz), 7.28–7.20 (1 H, m), 7.19 (1 H, bs), 6.92 (2 H, d, J =
8.8 Hz), 4.05–3.98 (2 H, m), 3.78 (3 H, s), 3.66 (3 H, s); 13C NMR
(75 MHz) (Acetone-d6) d 170.8, 168.6, 168.5, 161.0, 160.5, 160.1,
141.1, 135.2, 134.0, 131.0, 130.9, 130.3, 129.8, 129.7, 129.7, 127.0,
124.1, 121.1, 118.9, 115.7, 114.9, 60.6, 55.6, 52.3, 42.0; MS (ESI-)
m/z 480 (M-1, 100%); HRMS (ESI-) for C28H22N3O5, calculated
480.1638 found 480.1636.
122.9, 117.8, 116.1, 115.3, 106.0, 53.6, 32.3, 20.6, 20.5, 18.8, 18.4,
13.7, 13.5, 10.4, 10.0; MS (ESI-) m/z 501 (M-1, 100%); HRMS
(ESI+) for C32H29N4O2, calculated 502.2369 found 502.2369.
2-(2-Acetylphenylamino)-2-(4-nitrophenyl)-N-(pentan-2-yl)acet-
amide (25a) and 2-(3-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)-
2-(4-nitrophenyl)-N-(pentan-2-yl)acetamide (25b). Synthesized
utilizing the general procedure described above, from 1-(2-
aminophenyl)ethanone (0.57 g, 4.19 mmol), 4-nitrobenzaldehyde
(0.63 g, 4.19 mmol), cyanoacetic acid (0.35 g, 4.19 mmol) and
2-pentylisocyanide (0.50 g, 4.19 mmol) in MeOH (5.0 mL). The
crude reaction material was subjected to flash silica gel column
chromatography (4 : 1 hexanes–EtOAc) to afford 25a (0.68 g, 42%)
as a yellow solid (mp 237–239 ◦C). IR (KBr) 3268 (NH), 3075
(CH), 2964, 2933 (CH), 1649, 1642 (CO), 1560 (NO2), 1519, 1511
1
(NH), 1346 (NO2), 748 (CH). H NMR (300 MHz) (DMSO-d6)
d 9.86–9.71 (1 H, m), 8.34–8.26 (1 H, m), 8.21 (2 H, d, J = 8.9
Hz), 7.85 (1 H, dd, J = 8.0, 1.2 Hz), 7.80–7.68 (2 H, m), 7.26 (1
H, t, J = 7.2 Hz), 6.60 (1 H, t, J = 7.5 Hz), 6.38 (1 H, dd, J =
8.2, 5.6 Hz), 5.43–5.31 (1 H, m), 3.78–3.63, 3.54–3.43 (1 H, m,
d.r. 3 : 1), 2.56 (3 H, s), 1.32–1.18 (2 H, m), 1.06, 0.89 (3 H, d, J =
6.6 Hz, d.r. 1 : 3), 0.86–0.77 (2 H, m), 0.64, 0.50 (3 H, t, J = 7.3
Hz) 13C NMR (75 MHz) (DMSO-d6) d 200.6, 168.2, 167.6, 167.6,
147.7, 147.2, 147.0, 134.8, 133.1, 127.7, 123.7, 123.7, 118.1, 115.1,
112.1, 59.0, 58.9, 51.8, 44.5, 44.3, 37.9, 30.6, 28.0, 26.8, 26.7, 20.6,
20.2, 18.7, 18.4, 13.7, 13.4, 10.3, 9.8; MS (ESI+) m/z 384 (M+1,
100%); HRMS (ESI+) for C21H26N3O4, calculated 384.1845 found
384.1844.
2-(2-Benzoylphenylamino)-2-(1-methyl-1H-indol-3-yl)-N-(pen-
tan-2-yl)acetamide (24a) and 2-(3-cyano-2-oxo-4-phenylquinolin-
1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide
(24b). Synthesized utilizing the general procedure described
above, from 2-aminobenzophenone (0.52 g, 2.66 mmol), 1-methyl-
1H-indole-3-carbaldehyde (0.42 g, 2.66 mmol), cyanoacetic acid
(0.23 g, 2.66 mmol) and 2-pentylisocyanide (0.32 mL, 2.66 mmol)
in MeOH (5.0 mL). The crude material was subjected to silica
gel column chromatography (1 : 1 hexanes–EtOAc) to afford 24a
Further elution (1 : 1 hexanes–EtOAc) afforded 25b (0.47 g,
26%) as a cream solid (mp 248–249 ◦C). IR (KBr) 3323 (NH),
3078 (CH), 2963, 2930 (CH), 2227 (CN), 1687, 1632 (CO), 1608
1
(CC), 1558 (NO2), 1518 (NH), 1346 (NO2), 756 (CH) cm-1. H
NMR (300 MHz) (DMSO-d6) d 8.14 (2 H, d, J = 8.9 Hz), 8.04
(1 H, dd, J = 8.4, 0.9 Hz), 8.00–7.83 (1 H, m), 7.64–7.55 (3 H,
m), 7.36 (1 H, t, J = 7.6 Hz), 7.29–7.18 (1 H, m), 7.07 (1 H, bs),
3.93–3.73, 3.40–3.29 (1 H, m, d.r. 3 : 1), 2.82 (3 H, s), 1.51–1.08 (4
H, m), 1.04, 0.86 (3 H, d, J = 7.1 Hz, d.r. 1 : 3), 0.61, 0.39 (3 H,
t, J = 7.3, 7.3 Hz, d.r. 3 : 1); 13C NMR (75 MHz) (DMSO-d6) d
165.0, 158.6, 158.0, 158.0, 146.6, 142.0, 141.9, 138.8, 133.2, 129.6,
127.5, 123.3, 122.8, 119.9, 116.7, 116.6, 115.4, 106.1, 58.8, 44.9,
44.7, 37.8, 37.2, 30.5, 26.7, 25.9, 20.5, 20.0, 19.0, 18.3, 18.1, 13.7,
13.5, 10.6, 9.7; MS (ESI-) m/z 431 (M-1, 100%); HRMS (ESI-)
for C24H23N4O4, calculated 431.1798 found 431.1798.
◦
(0.37 g, 31%) as a yellow solid (mp 197–199 C). IR (KBr) 3263
(NH), 3078 (CH), 2956, 2928 (CH), 1648, 1621 (CO), 1555 (NH),
1251, 1181 (CO), 750, 739 (CH) cm-1. 1H NMR (300 MHz)
(DMSO-d6) d 9.24 (1 H, d, J = 5.2 Hz), 8.14–7.96 (1 H, m),
7.88–7.73 (1 H, m), 7.62–7.44 (6 H, m), 7.42–7.29 (4 H, m), 7.14
(1H, t, J = 7.4 Hz), 7.05–6.95 (1 H, m), 6.90–6.79 (1 H, m), 6.53 (1
H, t, J = 7.4 Hz), 5.57–5.35 (1 H, m), 3.35 (3 H, s), 1.33–1.17 (2 H,
m), 1.06, 0.89 (3 H, d, J = 6.6 Hz, dr 3 : 1), 0.87–0.76 (2 H, m), 0.64,
0.50 (3 H, t, J = 7.3 Hz, dr 3 : 1); 13C NMR (75 MHz) (DMSO-d6) d
198.0, 169.4, 149.7, 149.6, 139.9, 136.7, 134.7, 131.1, 130.9, 128.5,
128.1, 125.7, 121.3, 119.4, 118.8, 117.2, 114.1, 112.3, 111.4, 109.7,
53.6, 44.2, 44.2, 38.1, 37.9, 32.3, 26.7, 20.6, 20.5, 18.8, 18.4, 13.7,
13.5, 10.4, 10.0; MS (ESI+) m/z 454 (M+1, 100%); HRMS (ESI+)
for C29H32N3O2, calculated 454.2416 found 454.2416.
Further elution (1 : 1 hexanes–EtOAc) afforded 24b (0.38 g,
28%) as a yellow solid (mp 218–220 ◦C). IR (KBr) 3327 (NH), 3056
(CH), 2961, 2929 (CH), 2227 (CN), 1659 (CO), 1594 (CC), 1519
(NH), 763, 754, 741 (CH) cm-1. 1H NMR (300 MHz) (DMSO-d6)
d 7.67–7.61 (3 H, m), 7.60–7.50 (3 H, m), 7.49–7.39 (2 H, m), 7.38–
7.31 (1 H, m), 7.26–7.18 (1 H, m), 7.13–7.07 (1 H, m), 7.06–6.98 (1
H, m), 6.94–6.88 (2 H, m), 4.12–3.93 (1 H, m), 3.77 (3 H, s), 1.52–
1.34 (2 H, m), 1.19–1.08 (3 H, m), 0.95–0.84 (2 H, m), 0.74, 0.66 (3
H, t, J = 7.3 Hz, dr 3 : 1); 13C NMR (75 MHz) (DMSO-d6) d 160.2,
158.5, 158.4, 139.8, 133.7, 130.1, 129.8, 129.2, 128.7, 128.5, 127.9,
Methyl-2-(2-(2-acetylphenylamino)-2-(4-chlorophenyl)acetami-
do)acetate (26). Synthesized utilizing the general procedure
described above, from 1-(2-aminophenyl)ethanone (0.80 mL,
6.54 mmol), 4-chlorobenzaldehyde (0.92 g, 6.54 mmol),
cyanoacetic acid (0.56 g, 6.54 mmol) and methylisocyanoacetate
(0.80 mL, 6.54 mmol) in MeOH (5.0 mL) to afford 26 (1.43 g, 58%)
as a pale yellow solid (mp 239–240 ◦C). IR (KBr) 3358 (NH), 3078
(CH), 2954, 2939 (CH), 1746 (COC), 1643 (CO), 1563, 1511 (NH),
1232 (COC), 754 (CH) cm-1. 1H NMR (300 MHz) (DMSO-d6) d
9.65 (1 H, d, J = 6.7 Hz), 8.81 (1 H, t, J = 5.8 Hz), 7.84 (1 H, dd, J =
8.0, 1.1 Hz), 7.49 (2 H, d, J = 8.5 Hz), 7.41 (2 H, d, J = 8.5 Hz), 7.29
(1 H, t, J = 7.7 Hz), 6.66 (1 H, t, J = 7.5 Hz), 6.48 (1 H, d, J = 8.4
Hz), 5.31 (1 H, d, J = 6.7 Hz), 3.98–3.79 (2 H, m), 3.58 (3 H, s), 2.55
(3 H, s); 13C NMR (75 MHz) (DMSO-d6) d 200.6, 170.0, 169.8,
147.9, 137.7, 134.8, 132.9, 132.4, 128.6, 128.5, 118.0, 115.0, 112.2,
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58.5, 51.7, 40.6, 28.0; MS (ESI+) m/z 375 (M+1, 100%); HRMS
acid (0.36 g, 4.30 mmol) and 2,6-dimethylphenylisocyanide (0.56 g,
(ESI+) for C19H20ClN2O4, calculated 375.1033 found 375.1033.
4.30 mmol) in MeOH (5.0 mL) to afford 30 (0.88 g, 51%) as a pale
◦
yellow solid (mp 184–185 C). IR (KBr) 3446, 3217 (NH), 3027
2-(2-Benzoylphenylamino)-2-(4-chlorophenyl)-N-(2,6-dimethyl-
phenyl)acetamide (27). Synthesized utilizing the general pro-
cedure described above, from 2-aminobenzophenone (0.60 g,
3.00 mmol) 4-chlorobenzaldehyde (0.42 g, 3.00 mmol),
cyanoacetic acid (0.25 g, 3.00 mmol) and 2,6-dimethyl-
phenylisocyanide (0.40 g, 3.00 mmol) in MeOH (5.0 mL) to afford
27 (1.04 g, 74%) as a yellow solid (mp 168–170 ◦C). IR (KBr) 3446,
3244 (NH), 3061 (CH), 1655, 1625 (CO), 1565, 1515 (NH), 748
(CH), 699(CCl); 1H NMR (300 MHz) (DMSO-d6) d 9.82 (1 H, s),
9.44 (1 H, d, J = 6.5 Hz), 7.70 (2 H, d, J = 8.3 Hz), 7.62–7.46 (7
H, m), 7.44–7.32 (2 H, m), 7.11–6.94 (3 H, m), 6.69 (1 H, d, J =
8.4 Hz), 6.60 (1 H, t, J = 7.5 Hz), 5.55 (1 H, d, J = 6.5 Hz), 1.91
(6 H, bs); 13C NMR (75 MHz) (DMSO-d6) d 198.2, 167.9, 148.6,
139.6, 138.0, 135.1, 134.8, 134.7, 134.0, 132.6, 131.1, 128.7 (3C),
128.2, 127.7, 126.7, 117.8, 114.9, 112.6, 59.1, 17.6; MS (ESI+) m/z
469 (M+1, 100%); HRMS (ESI+) for C29H26ClN2O2, calculated
469.1605 found 469.1605.
(CH), 2924, 2859 (CH), 1645 (CO), 1562 (NH), 1520, 1348 (NO2),
763 (CH) cm-1. 1H NMR (300 MHz) (DMSO-d6) d 10.00¢9.82 (2
H, m), 8.29 (2 H, d, J = 8.7 Hz), 7.98–7.82 (3 H, m), 7.32 (1 H,
t, J = 7.7 Hz), 7.10–6.95 (3 H, m), 6.65 (1 H, t, J = 7.4 Hz), 6.55
(1 H, d, J = 8.4 Hz), 5.67 (1 H, d, J = 6.6 Hz), 2.58 (3 H, s), 1.90
(6 H, bs); 13C NMR (75 MHz) (DMSO-d6) d 200.8, 167.1, 147.7,
147.2, 146.8, 135.0, 134.9, 133.8, 133.1, 128.1, 127.7, 126.8, 123.8,
118.3, 115.3, 112.3, 59.2, 28.0, 17.6; MS (ESI+) m/z 418 (M+1,
100%); HRMS (ESI+) for C24H24N3O4, calculated 418.1689 found
418.1691.
2-(2-Acetylphenylamino)-N -(naphthalen-2-yl)-2-(4-nitrophe-
nyl)acetamide (31). Synthesized utilizing the general proce-
dure described above, from 1-(2-aminophenyl)ethanone (0.17 g,
1.40 mmol), 4-nitrobenzaldehyde (0.21 g, 1.40 mmol), cyanoacetic
acid (0.12 g, 1.40 mmol) and 2-isocyanonaphthalene (0.22 g,
1.40 mmol) in MeOH (5.0 mL) to afford 31 (0.35 g, 57%) as a
◦
light brown solid (mp 242–244 C). IR (KBr) 3447, 3259 (NH),
2-(2-Benzoylphenylamino)-N-(2,6-dimethylphenyl)-2-(4-nitro-
phenyl)acetamide (28). Synthesized utilizing the general pro-
cedure described above, from 2-aminobenzophenone (0.60 g,
3.00 mmol), 4-nitrobenzaldehyde (0.45 g, 3.00 mmol), cyanoacetic
acid (0.25 g, 3.00 mmol) and 2,6-dimethylphenylisocyanide (0.40 g,
3.00 mmol) in MeOH (5.0 mL) to afford 28 (0.78 g, 54%) as a
3074 (CH), 1665, 1641 (CO), 1561 (NH), 1519, 1346 (NO2), 751
(CH) cm-1. 1H NMR (300 MHz) (DMSO-d6) d 10.80 (1 H, s), 9.96
(1 H, d, J = 6.8 Hz), 8.29–8.21 (3 H, m), 7.92–7.84 (4 H, m), 7.82
(2 H, d, J = 8.2 Hz), 7.58 (1 H, dd, J = 8.8, 1.3 Hz), 7.50–7.28 (3
H, m), 6.66 (1 H, t, J = 7.5 Hz), 6.52 (1 H, d, J = 8.5 Hz), 5.67 (1
H, d, J = 6.8 Hz), 2.59 (3 H, s); 13C NMR (75 MHz) (DMSO-d6) d
200.9, 167.5, 147.6, 147.2, 146.2, 135.6, 135.0, 133.1, 130.0, 128.5,
128.0 (2C), 127.4, 127.3, 126.5, 124.9, 124.0, 119.7, 118.3, 115.9,
115.4, 112.1, 59.6, 28.0; MS (ESI+) m/z 440 (M+1, 100%); HRMS
(ESI+) for C26H22N3O4, calculated 440.1532 found, 440.1532.
◦
yellow solid (mp 226–228 C). IR (KBr) 3447, 3234 (NH), 3059
(CH), 2923, 2853 (CH), 1653, 1624 (CO), 1568 (NH), 1510, 1345
(NO2), 750 (CH) cm-1. 1H NMR (300 MHz) (DMSO-d6) d 9.97 (1
H, s), 9.55 (1 H, d, J = 6.5 Hz), 8.32 (2 H, d, J = 8.5 Hz), 7.96 (2 H,
d, J = 8.5 Hz), 7.68–7.48 (5 H, m), 7.46–7.33 (2 H, m), 7.09–6.95
(3 H, m), 6.72–6.57 (2 H, m), 5.74 (1 H, d, J = 6.5 Hz), 1.90 (6
H, bs); 13C NMR (75 MHz) (DMSO-d6) d 198.1, 167.2, 148.4,
147.3, 146.8, 139.6, 135.2, 135.1, 134.9, 133.9, 131.3, 128.8, 128.3
(2C), 127.9, 126.9, 124.0, 118.0, 115.3, 112.7, 59.3, 17.7; MS (ESI+)
m/z 480 (M+1, 100%); HRMS (ESI+) for C29H26N3O4, calculated
480.1845 found 480.1845.
2-(2-Acetylphenylamino)-2-(4-methoxyphenyl)-N-(naphthalen-
2-yl)acetamide (32). Synthesized utilizing the general procedure
described above, from 1-(2-aminophenyl)ethanone (0.17 mL,
1.38 mmol), 4-methoxybenzaldehyde (0.17 mL, 1.38 mmol),
cyanoacetic acid (0.11 g, 1.38 mmol) and 2-isocyanonaphthalene
(0.21 g, 1.38 mmol) in MeOH (5.0 mL) to afford 32 (0.41 g, 70%)
as a light brown solid (mp 184–185 ◦C). IR (KBr) 3452, 3264
(NH), 2998, 2958 (CH), 1655, 1643 (CO), 1558, 1509 (NH), 1244
(CO) cm-1. 1H NMR (300 MHz) (DMSO-d6) d 10.57 (1 H, s), 9.80
(1 H, d, J = 6.7 Hz), 8.27 (1 H, s), 7.93–7.75 (5 H, m), 7.59 (1 H,
dd, J = 8.8, 1.8 Hz), 7.52 (2 H, d, J = 8.6 Hz), 7.49–7.27 (4 H,
m), 6.94 (2 H, d, J = 8.7 Hz), 6.63 (1 H, d, J = 7.7 Hz), 6.58 (1
H, d, J = 8.0 Hz), 5.40 (1 H, d, J = 6.7 Hz), 3.70 (3H, s), 2.58
(3 H, s); 13C NMR (75 MHz) (DMSO-d6) d 200.6, 169.1, 158.9,
148.2, 136.0, 134.8, 133.2, 133.0, 130.3, 129.8, 128.4, 127.9, 127.3,
127.2, 126.4, 124.7, 119.8, 118.0, 115.6, 114.8, 114.1, 112.1, 59.4,
55.0, 28.0; MS (ESI+) m/z 425 (M+1, 100%); HRMS (ESI+) for
C27H25N2O3, calculated 425.1787, found 425.1787.
2-(2-Acetylphenylamino)-N-(2,6-dimethylphenyl)-2-(4-metho-
xyphenyl)acetamide (29). Synthesized utilizing the general pro-
cedure described above, from 1-(2-aminophenyl)ethanone (0.60 g,
4.40 mmol), 4-methoxybenzaldehyde (0.60 g, 4.40 mmol),
cyanoacetic acid (0.38 g, 4.40 mmol) and 2,6-dimethyl-
phenylisocyanide (0.60 g, 4.40 mmol) in MeOH (5.0 mL) to afford
29 (1.14 g, 69%) as a pale yellow solid (mp 184–185 ◦C). IR (KBr)
3446, 3212 (NH), 3030 (CH), 2961, 2931 (CH), 1645 (CO), 1564,
1
1508 (NH), 1244 (CO), 762 (CH) cm-1. H NMR (300 MHz)
(DMSO-d6) d 9.79–9.54 (2 H, m), 7.85 (1 H, d, J = 8.1 Hz), 7.51
(2 H, d, J = 8.3 Hz), 7.33 (1 H, t, J = 7.7 Hz), 7.10–6.83 (5 H,
m), 6.71–6.49 (2 H, m), 5.35 (1 H, d, J = 3.6 Hz), 3.73 (3 H, s),
2.55 (3 H, s), 1.90 (6 H, bs); 13C NMR (75 MHz) (DMSO-d6) d
200.5, 168.7, 158.9, 148.2, 135.1, 134.7, 134.2, 133.1, 133.0, 130.8,
128.0, 127.6, 126.5, 118.0, 114.9, 114.7, 113.9, 112.4, 59.1, 55.0,
28.0, 17.6; MS (ESI+) m/z 403 (M+1, 100%); HRMS (ESI+) for
C25H27N2O3, calculated 403.1943 found 403.1944.
Ethyl-3-(2-(2-acetylphenylamino)-2-(4-nitrophenyl)acetamido)-
propanoate (36). Synthesized utilizing the general procedure
described above, from 1-(2-aminophenyl)ethanone (0.35 mL,
2.80 mmol), 4-nitrobenzaldehyde (0.42 g, 2.80 mmol), cyanoacetic
acid (0.24 g, 2.80 mmol) and ethyl isocyanopropionate (0.36 mL,
2.80 mmol) in MeOH (5.0 mL) to afford 36 (0.67 g, 58%) as a pale
2-(2-Acetylphenylamino)-N -(2,6-dimethylphenyl)-2-(4-nitro-
phenyl)acetamide (30). Synthesized utilizing the general proce-
dure described above, from 1-(2-aminophenyl)ethanone (0.58 g,
4.30 mmol), 4-nitrobenzaldehyde (0.65 g, 4.30 mmol), cyanoacetic
◦
yellow solid (mp 262–263 C). IR (KBr) 3452, 3250 (NH), 1724
(COO), 1644 (CO), 1561 (NH), 1520, 1349 (NO2), 1240 (CO) cm-1.
1H NMR (300 MHz) (DMSO-d6) d 9.77 (1 H, d, J = 6.3 Hz), 8.62
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(1 H, s), 8.18 (2 H, d, J = 7.9 Hz), 7.83 (1 H, d, J = 7.9 Hz), 7.71
(2 H, d, J = 7.9 Hz), 7.24 (1 H, t, J = 7.5, 7.5 Hz), 6.59 (1 H, t, J =
7.3, 7.3 Hz), 6.39 (1 H, d, J = 8.3 Hz), 5.37 (1 H, d, J = 6.3 Hz),
3.94 (2 H, q, J = 6.7 Hz), 3.37–3.24 (2 H, m), 2.55 (3 H, s), 2.40 (2
H, t, J = 5.8 Hz), 1.06 (3 H, t, J = 6.9 Hz); 13C NMR (75 MHz)
(DMSO-d6) d 200.7, 170.9, 168.6, 147.6, 147.0, 146.7, 134.8, 133.0,
127.8, 123.6, 118.1, 115.1, 112.1, 59.8, 58.8, 34.9, 33.2, 27.9, 13.7;
MS (ESI+) m/z 414 (M+1, 100%); HRMS (ESI+) for C21H24N3O6,
calculated 414.1587 found, 414.1585.
7.92–7.85 (1 H, m), 7.51–7.46 (1 H, m), 7.45–7.29 (2 H, m), 7.24–
7.14 (2 H, m), 7.02–6.90 (1 H, m), 6.87–6.75 (1 H, m), 5.59 (1 H,
s), 4.01 (2 H, q, J = 7.1 Hz), 3.61–3.32 (2 H, m), 2.54–2.40 (2 H,
m), 2.25–2.12 (3 H, m), 2.14 (3 H, s), 1.14 (3 H, t, J = 7.1 Hz);
13C NMR (75 MHz) (Acetone-d6) d 197.9, 170.7, 170.6, 168.9,
168.8, 166.1, 165.9, 164.9, 146.9, 143.8, 143.6, 141.4, 140.9, 140.5,
136.9, 136.6, 132.9, 131.9, 131.6, 130.2, 129.7, 129.3, 128.0, 122.8,
122.8, 122.3, 121.9, 63.9, 59.4, 59.3, 41.3, 34.8, 34.7, 33.1, 31.2,
28.9, 28.7, 27.8, 21.9, 16.8, 16.5, 13.0, 13.0; MS (ESI+) m/z 482
(M+1, 100%); HRMS (ESI+) for C25H28N3O7, calculated 482.1849
found, 482.1851.
(Z)-Ethyl-3-cyano-4-(4-nitrophenyl)but-3-enoate (38). Synthe-
sized utilizing the general procedure described above, from 1-
(2-aminophenyl)ethanone (0.33 mL, 2.77 mmol), 4-nitrobenzal-
dehyde (0.42 g, 2.77 mmol), 2-ethylcyanoacetate (0.24 mL,
2.77 mmol) and ethyl isocyanopropionate (0.35 mL, 2.77 mmol)
in MeOH (5.0 mL) to afford 38 (0.41 g, 64%) as a pale yellow
solid (mp 262–263 ◦C). IR (KBr) 3444 (OH), 3119 (CH), 2225
(CN), 1718 (CO), 1612 (CC), 1529, 1346 (NO2), 1228 (CO) cm-1.
1H NMR (300 MHz) (DMSO-d6) d 8.49 (1 H, s), 8.35 (2 H, d,
J = 8.7 Hz), 8.19 (2 H, d, J = 8.7 Hz), 3.87 (2 H, s); 13C NMR (75
MHz) (DMSO-d6) d 161.5, 152.5, 149.1, 137.0, 131.5, 124.0, 114.7,
106.2, 53.5; MS (ESI+) m/z 233 (M+1, 100%); HRMS (ESI+) for
C11H9N2O4, calculated 233.0484 found, 233.0484.
Ethyl-3-(2-(N-(2-benzoylphenyl)-3,3,3-trifluoropropanamido)-
2-(4-nitrophenyl)acetamido)propanoate (43). Synthesized utiliz-
ing the general procedure described above, from 1-(2-amino-
phenyl)ethanone (0.40 mL, 3.20 mmol), 4-nitrobenzaldehyde
(0.49 g, 3.20 mmol), 3,3,3-trifluoropropanoic acid (0.30 mL,
3.20 mmol) and ethyl isocyanopropionate (0.41 mL, 3.20 mmol)
in MeOH (5.0 mL) to afford 43 (0.841 g, 50%) as a yellow solid
(mp 152–154 ◦C). 1H NMR (300 MHz) (DMSO-d6) d 7.95 (2 H,
d, J = 8.8 Hz), 7.88 (1 H, d, J = 7.8), 7.62 (1 H, ddd, J = 7.7,
7.7, 1.7 Hz), 7.52 (1 H, ddd, J = 7.8, 7.8, 1.6 Hz), 7.49 (1 H, d,
J = 8.9 Hz), 7.48–7.40 (1 H, m), 7.31–7.25 (2 H, m), 6.05 (1 H, s),
4.20–4.02 (2 H, m), 3.67–3.42 (2 H, m), 2.61–2.50 (3H, m), 2.12
(3H, s) 1.21 (3 H, t, J = 7.1); 13C NMR (75 MHz) (DMSO-d6) d
199.0, 170.9, 168.7, 163.5, 146.9, 140.8, 135.8, 135.5, 133.4, 133.0,
131.7, 130.4, 129.3, 123.2, 122.7, 62.5, 59.8, 34.9, 33.3, 28.8, 13.8;
MS (ESI+) m/z 524.
Ethyl-3-(2-(N-(2-acetylphenyl)but-2-ynamido)-2-(4-nitrophe-
nyl)acetamido)propanoate (41). Synthesized utilizing the gen-
eral procedure described above, from 1-(2-aminophenyl)ethanone
(0.43 g, 3.20 mmol), 4-nitrobenzaldehyde (0.49 g, 3.20 mmol), 2-
butynoic acid (0.27 g, 3.20 mmol) and ethyl isocyanopropionate
(0.41 mL, 3.20 mmol) in MeOH (5.0 mL). The crude reaction
material was subjected to flash silica gel chromatography (1 : 1
hexanes–EtOAc) to afford 41 (0.91 g, 60%) as a yellow oil. IR
(KBr) 3399 (NH), 3114 (CH), 2982 (CH), 2231 (CC), 1725, 1673,
1644 (CO), 1516, 1363 (NO2), 1190 (CO), 761 (CH) cm-1. 1H NMR
(300 MHz) (Acetone-d6) d 8.28 (2 H, d, J = 8.8 Hz), 8.24 (2 H,
d, J = 8.8 Hz), 7.95 (2 H, d, J = 8.8 Hz), 7.84 (1 H, dd, J = 7.9,
1.0 Hz), 7.76 (1 H, t, J = 5.8, 5.8 Hz), 7.72–7.62 (3 H, m), 7.49 (2
H, d, J = 8.8 Hz), 7.34 (1 H, dt, J = 7.6, 1.1 Hz), 6.09 (1 H, s),
6.01 (1 H, s), 4.23–3.79 (4 H, m), 3.64–3.46 (4 H, m), 2.68–2.46
(4 H, m), 2.39 (3 H, s), 2.02 (1 H, s), 1.65 (1 H, s), 1.23–1.08 (4
H, m), 0.88 (6 H, m); 13C NMR (75 MHz) (Acetone-d6) d 197.9,
170.7, 170.6, 170.3, 170.1, 168.3, 167.3, 167.3, 154.3, 153.9, 153.1,
147.3, 147.1, 146.9, 142.7, 142.6, 140.7, 136.7, 136.3, 132.6, 131.6,
129.9, 129.7, 129.1, 128.1, 123.2, 122.9, 122.5, 121.9, 89.8, 89.4,
88.7, 73.8, 72.5, 72.3, 64.0, 63.8, 60.2, 59.5, 59.5, 59.4, 59.3, 42.9,
39.8, 34.9, 33.8, 33.0, 31.6, 31.2, 29.0, 28.2, 27.7, 21.9, 13.1, 13.0;
MS (ESI+) m/z 480 (M+1, 100%); HRMS (ESI+) for C25H26N3O7,
calculated 480.1693 found, 480.1693.
Acknowledgements
This work was supported by the Australian Research Council.
K.A.Y. and L.H. gratefully acknowledge scholarship support from
John Morris Scientific (Australia).
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(CH). H NMR (300 MHz) (Acetone-d6) d 8.28–8.11 (2 H, m),
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