A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides

Article abstract of DOI:10.1039/c9ra00118b

The Ugi four component reaction of an aldehyde, amine, isocyanide and an ethanoic acid was effected smoothly in protic ionic liquids ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) to afford analogues of α-phenylacetamido amides in good to ex

Full text of DOI:10.1039/c9ra00118b

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A methanol and protic ionic liquid Ugi
multicomponent reaction path to cytotoxic a-
phenylacetamido amides†
Cite this: RSC Adv., 2019, 9, 7652
Ahmed Al Otaibi,‡a Fiona M. Deane,a Cecilia C. Russell,a Lacey Hizartzidis,a
a
Siobhann N. McCluskey,a Jennette A. Sakoffb and Adam McCluskey
*
The Ugi four component reaction of an aldehyde, amine, isocyanide and an ethanoic acid was effected
smoothly in protic ionic liquids ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) to
afford analogues of a-phenylacetamido amides in good to excellent isolated yields. The
corresponding reactions in [BMIM][PF6] and the protic ionic liquid ethanolammonium nitrate (ETAN)
failed. Microwave irradiation in EAN facilitated rapid access to three focused libraries, based on the
parent isocyanide: cyclohexyl isocyanide, benzyl isocyanide and ethyl isocyanoacetate. Analysis of
the structure activity relationship data suggested the presence of a bulky moiety originating from
the isocyanide (cyclohexyl and benzyl) enhanced cytotoxicity. Removal of the acetylenic H-atom
from the ethanoic acid moiety was detrimental to cytotoxicity. The most active analogues
Received 6th January 2019
Accepted 4th February 2019
produced,
N-(2-cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl-N-(3,5-dimethoxyphenyl)
propiolamide, returned average GI50 values of #1 mM across the cancer cell lines evaluated.
Combined, these data suggest that analogues of this nature are interesting potential anti-cancer
development leads.
DOI: 10.1039/c9ra00118b
rsc.li/rsc-advances
and require fewer resources, less time, energy and human
effort. In many cases simpler purication processes and high
convergence are also evident.13,21–24 Isocyanide-based MCRs are
one of the most important and widely used of all the MCRs, and
have been extensively used in the development of biologically
active compounds.4,13,24–28
The Ugi reaction is a well explored MCR for the generation of
peptide like adducts,29–33 and as others and we have previously
reported for the synthesis of heterocycles, e.g. quninolin-2-(1H)-
ones and tetrahydroepoxisindole carboxamides.34,35 In these
programs we have an on-going interest in the development of
cytotoxic compounds, as have others. Previously Yamada et al.
demonstrated the 4-component Ugi reaction provided robust
access to a small library of cytotoxic propynoic acid carbamoyl
methyl amide (PCMA) derivatives such as 1 and 2 (Fig. 1).36
Introduction
The ability to rapidly probe the subtle nuances of chemical
space through the decoration of simple and complex chemical
scaffolds is critical to the development of new therapeutics and
new therapeutic lead compounds.1–7 Medicinal chemistry relies
on a robust toolkit of chemical modication broadly applicable
across a diverse array of chemotypes. These robust, reliable
synthetic tools enable rapid development of structure activity
relationship data, the installation of favourable physicochem-
ical properties and the bioisosteric replacement of toxicophores
that may stymy drug development endeavours.8–10
Multicomponent reactions (MCRs) are key ‘medicinal tool-
kit’ reactions permitting rapid assembly of three or more
components in
a one-pot sequence to produce a nal
product.11–20 MCRs present the medicinal chemist with addi-
tional benets beyond rapid compound access and diversity,
they are typically highly atom economic producing less waste
aChemistry, School of Environmental & Life Sciences, The University of Newcastle,
University Drive, Callaghan, NSW 2308, Australia. E-mail: Adam.McCluskey@
newcastle.edu.au
bDepartment of Medical Oncology, Calvary Mater Newcastle Hospital, Edith Street
Waratah 2298, Australia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra00118b
Fig. 1 Two examples for cytotoxic propynoic acid carbamoyl methyl
amides (PCMA) synthesised by Yamada,36 and 3-component Ugi
product from Gordon et al.34
‡ Present address: Department of Chemistry, Faculty of Science, University of
Hail, Hail, Kingdom of Saudi Arabia.
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Table 3 The effect of PIL, microwave irradiation time and temperature
on the yield of the Ugi coupling of 5, 7, 10 and 11 to yield 12
Irradiation time
10 min
20 min
5 min
Scheme 1 Reagents and conditions: CH3OH, rt.
Entry
PIL
50 ꢀ
C
100 ꢀC
120 ꢀ
C
120 ꢀ
C
120 ꢀ
C
a
1
2
3
EAN
PAN
ETAN
—
58%
51%
—
60%
55%
—
62%
60%
—
61%
54%
—
a
—
Table 1 Effect of microwave irradiation time and reaction tempera-
ture on the isolated yield of the Ugi coupling of 5, 7, 10 and 11 in
methanol to yield 12
a
a
a
a
a
—
a
No reaction, starting material recovered.
Entry
Time (min)
Temp. ꢀC
Yield%
1
2
3
4
5
6
7
5
5
5
10
20
30
1 h
50
100
120
120
120
120
120
11
58
63
69
83
78
70
Results and discussion
The PCMA compounds 1 and 2 in Fig. 1 are related to a series of
Ugi-products that we previously reported differing primarily the
incorporation of an aminoketone, e.g. 3,34 but with these
analogues we did not examine the cytotoxicity. In our hands
a typical synthesis of this type of compound comprised the
stirring of a methanolic solution of 2-aminobenzophenone (4)
with benzaldehyde (5) followed by the addition of cyanoacetic
acid (6) and cyclohexylisocyanide (7) afforded access to a sepa-
rable mixture of the Ugi product, 8 and the Ugi-Knoevenagel
product 9, Scheme 1. However, each reaction required 48 h to
afford a modest 55% isolated yield.34
As one of our team's drivers is enhancing green approaches
to biologically active compounds, we explored alternative
approaches that have been shown in other instances to
Scheme 2 Reagents and conditions: CH3OH, rt – 120 ꢀC.
Table 2 Evaluation of the cytotoxicity (GI50 (mM)) of a-amino amide analogue (13) and quninolin-2-(1H)-one analogues (14 and 15) against
a panel of ten cancer cell lines. GI50 is the concentration of drug that reduces cell growth by 50% relative to an untreated control
Compound
HT29a
SW480a
MCF-7b
A2780c
H460d
A431e
Du145f
BE2-Cg
SJ-G2h
MIAi
6.4 ꢁ 0.8
6.0 ꢁ 0.4
6.0 ꢁ 2.5
7.0 ꢁ 1.5
12 ꢁ 0
11 ꢁ 0
11 ꢁ 1
5.4 ꢁ 0.9
6.7 ꢁ 0.9
6.9 ꢁ 1.2
5.3 ꢁ 0.3
8.7 ꢁ 0.5
11 ꢁ 1
4.6 ꢁ 1.1
7.9 ꢁ 1.0
3.9 ꢁ 0.3
7.5 ꢁ 0.6
5.2 ꢁ 0.1
2.7 ꢁ 0.3
6.3 ꢁ 0.5
13 ꢁ 0
3.6 ꢁ 0.1
7.3 ꢁ 0.3
6.5 ꢁ 0.3
6.0 ꢁ 0.1
17 ꢁ 1
11 ꢁ 1
18 ꢁ 1
10 ꢁ 1
13 ꢁ 1
a
HT29 and SW480 (colon carcinoma). b MCF-7 (breast carcinoma). c A2780 (ovarian carcinoma). d H460 (lung carcinoma). e A431 (skin carcinoma).
Du145 (prostate carcinoma). g BE2-C (neuroblastoma). h SJ-G2 and U87 (glioblastoma). i MIA (pancreatic carcinoma).
f
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1
enhance, and accelerate, reaction efficiency.37–44 Microwave by H NMR analysis (ESI+). Irradiation of the reaction mixture
irradiation of a model system, only expected to produce the for 20 min at 120 ꢀC gave the desired 12 in an 83% isolated yield,
linear Ugi product, comprising 5, 7, 10 and 11 in methanol was representing a considerable enhancement over the initial 55%
ꢀ
ꢀ
ꢀ
evaluated at 50 C, 100 C and 120 C and the outcomes pre- yield and 48 h reaction time. Prolonged heating resulted in
sented in Table 1 (Scheme 2).45 Aer 5 min irradiation at 50 ꢀC a lower isolated yield, presumably a function of product
a precipitate was observed, however TLC analysis indicated degradation.
a mixture of product and starting materials. Increasing the
Expansion of the range of amines, acids, aldehydes and
ꢀ
ꢀ
reaction temperature to 100 C and then 120 C for 5 min saw isonitriles afforded access to a broader range of Ugi products
a signicant increase in product yield (58% and 63% respec- (Scheme 1; Table 2 and ESI† for detail). Subsequent MTT
tively), and in these instances the collected precipitate was pure phenotypic screening against a panel of ten cancer cell lines
Table 4 Isolated yields of a-amino amides from the Ugi reaction in EAN under microwave irradiation conditionsa
Product
Ethanolb (%) EANc (%) Product
Ethanolb (%) EANc (%) Product
Ethanolb (%) EANc (%)
83
76
58
66
70
67
54
69
71
75
60
64
65
78
73
60
49
56
51
45
71
67
70
79
51
55
41
61
68
66
66
58
51
54
69
59
45
36
41
30
50
45
a
b
Starting material recovered. At 120 ꢀC for 20 min and using MeOH. c At 120 ꢀC by using microwave and EAN for 10 min.
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revealed modest levels of cytotoxicity at a single 25 mM a modied panel of eleven tumour cell lines: colon (HT29,
compound concentration.46 Only
small number of SW480), skin (A431), lung (H460), ovarian (A2780), breast (MCF-
a
compounds, those with >80% growth inhibition at 25 mM 7), prostate (Du145), pancreatic (MIA), glioblastoma (SJ-G2,
against at least one cell line, from each of the a-amino amides SMA, U87), and neuroblastoma (BE2-C) and one non-cancer
(7) and quinolone (8) compound series being sufficiently active derived normal breast cell line (MCF10A). Compounds were
to proceed to full dose response evaluation (Table 2).
initially screened at 25 mM drug concentrations (ESI†), and from
While the observed cytotoxicity of 13, 14 and 15 was similar, this screening, analogues 12, 16d, 16g, 17a, 17e and 18a showed
with average GI50 values of 7.85, 6.18 and 10.7 mM respectively, sufficiently promising activity to warrant full dose evaluation,
access to the Ugi-Knoevenagel intramolecularly cyclised and these data are presented in Table 5.
product series was limited by the nature of the acid (requiring
Of the six analogues that proceeded to GI50 determination,
the presence of an acidic methylene moiety). Accordingly, we exemplars from each isocyanide (cyclohexylisocyanide, benzy-
limited further compound development and cytotoxicity lisocyanide and ethyl isocyanoacetate) library were present.
screening to new families of a-amino amides.
Four analogues contained an acetylene moiety (12, 16d, 17a and
Although microwave irradiation at 120 ꢀC afforded excellent 18a) with the other two derived from acetic (17e) and tri-
yields, this required the coupling to be conducted signicantly uoropropionic acid (16g). The cyclohexyl moiety was present in
above the boiling point of methanol with associated safety three of these analogues (12, 16d and 16g) and a benzyl moiety
concerns. Accordingly, we sought a less volatile solvent, of (17a and 17e) in two, suggesting a requirement for a bulky
which room temperature ionic liquids not only display the hydrophobic moiety on the right-hand side of the molecule (as
desired negligible to low vapour pressures, are environmentally drawn). Analogues retaining the acetylenic moiety (12, 17a and
friendly solvents, but as yet have not been explored for use in 18a) were considerably more potent than the equivalent prop-
the Ugi coupling.47 Thus, Ugi coupling of 5, 7, 10 and 11 was argylic analogue (16d) with average GI50 values of 1.16 mM, 0.97
explored in [BMIM][PF6]. Aer 24 h, despite allowing the imine mM, 1.8 mM and 9.4 mM respectively. With the acetylenic series
from 3 and 5 to pre-form (Scheme 2), no product was observed of compounds (12, 17a and 18a) sub-micro molar levels of
at room temperature by TLC analysis. The same outcome was toxicity is noted against HT29, U87, A2780, MIA and SMA cell
noted at 80 ꢀC even aer 24 h, but at 100 ꢀC and 120 ꢀC, 20% and lines. Removal of the acetylene (or propargylic) moiety with 17a
32% product recovery was noted, however this was only aer results in a >30 fold potency reduction (average GI50 value > 30
chromatographic separation.
mM), but the introduction of a triuoromethyl moiety with 16g
In previous imine formation studies in our laboratory we results in an analogue equipotent with 16d with an average GI50
noted an acceleration on imine formation on acid catalysis.35,48 of 7.2 mM (Table 5).
We thus rationalised that this Ugi coupling might thus proceed
Given the clear enhanced cytotoxicity of analogues contain-
more effectively in a protic ionic liquid.49,50 This is in keeping ing the acetylenic moiety, and the similarity to those from the
with prior reports of efficient multicomponent reactions in Yamada report,30 we sought to directly compare both analogues
ionic liquids and deep eutectic salts.51–55 The model coupling sets and expand the pharmacophore of these compounds. Thus,
described above in each of, ethylammonium nitrate (EAN), we in-house synthesised lead 1 and three additional methoxy
propylammonium nitrate (PAN) and ethanol ammonium analogues (19–21) as per Scheme 2. Screening data for these
nitrate (ETAN) with microwave irradiation was evaluated aer four analogues (1, 19–21) is presented in Table 5. Analysis of
ꢀ
ꢀ
ꢀ
5 min irradiation at 50 C, 100 C and 120 C (Table 2). Pleas- these data is consistent with the acetylene moiety analogues
ingly aer 5 min irradiation at 100 ꢀC, with EAN, a 58% recovery being sub-micromolar cytotoxic with all four analogues
of pure 12 was achieved, increasing to 60% at 120 ꢀC with returning average GI50 values # 1 mM for the cancer cell lines
a similar outcome noted with PAN. Interestingly ETAN was examined. Of note in this series of analogues was the removal of
ineffectual, presumably a consequence of the pendent OH the aromatic methoxy moieties that saw a reduction in the
moiety (Table 3). As EAN returned the highest yields of 12 at observed toxicity towards the MCF10A normal breast cell line.
both 100 ꢀC and 120 ꢀC, this PIL was used in subsequent This was most apparent on removal of those methoxy moieties
experiments.
originating from the starting aniline. Repositioning of the
Having demonstrated the efficacy of the Ugi coupling in this methoxy moieties to the starting benzaldehyde was tolerated in
model system, we next examined the production of three iso- this series of analogues, with both the 2,3- and 3,4-dimethoxy
cyanide derived compound libraries through the use of cyclo- disposed analogues showing a 10-fold selectivity for cancer the
hexyl isocyanide, benzyl isocyanide, and ethyl isocyanoacetate, cancer cell lines versus the MCF10A normal cell line. This is
respectively, and a suite of diverse acids; propiolic, methoxy- a promising level of selectivity at this stage of compound
acetic, crotonic, 2-butynoic, acetic, cyanoacetic and 3,3,3-tri- exploration.
uoropropionic acids while retaining the parent aniline and
benzaldehyde in the synthesis of three focused (12 and 16b–g;
17a–g; and 18a–g) libraries of a-amino amides (see Scheme 2).
Conclusions
In most instances the yields in EAN were comparable to that The Ugi coupling of an aldehyde, amine, isocyanide and etha-
obtained on microwave irradiation in MeOH at 120 ꢀC (Table 4). noic acid to afford analogues of a-phenylacetamido amides in
The cytotoxicity of the each of the focused libraries (12 and modest yield under microwave irradiation conditions in meth-
16b–g, 17a–g and 18a–g) compounds, were investigated in anol. Solvent switching to the protic ionic liquids EAN and PAN
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afforded higher or comparable yields without the need to heat 20A column heater, and a SPD-20A UV/vis detector. This
the reaction about the solvent boiling point as was the case with system was tted with an Alltima™ C18 5 mm 150 mm ꢂ 4.6 mm
the methanol reaction, with reactions conducted at 120 ꢀC. column with solvent A: 0.06% triuoroacetic acid (TFA) in water
Neither [BMIM][PF6] nor ETAN afforded useful yields of the and solvent B: 0.06% TFA in CH3CN–H2O (90 : 10). In each case
desired products. Our prior studies have shown that the initial HPLC traces were acquired at a ow rate of 2.0 mL minꢃ1
,
imine formation requires acid catalysis, with the free OH moiety gradient 10–100 (%B), over 15.0 min, with detection at 220 nm
of ETAN presumed to interfere with this reaction. The Ugi and 254 nm.
¨
Melting points were recorded on a Buchi Melting Point M-
coupling in the presence of an acid with an acidic methylene
moiety afforded an additional Ugi-Knoevenagel cyclised 565 instrument. IR spectra were recorded on a PerkinElmer
product, but given the need for the acid component to contain Spectrum Two™ FTIR Spectrometer with the UATR accessories.
an additional a-methylene requirement (which were of limited Thin layer chromatography (TLC) was performed on Merck 60
supply in our laboratory), our subsequent synthesis was F254 pre-coated aluminium plates with a thickness of 0.2 mm.
directed at the four component Ugi products. From this, three Column chromatography was performed under ‘ash’ condi-
focused libraries, based on the starting cyclohexylisocyanide, tions on Merck silica gel 60 (230–400 mesh).
benzylisocyanide and ethyl isocyanoacetate, were produced in
good to excellent yield.
In vitro growth inhibition assays
The acetylene containing 12, 16d, 17a and 18a; acetic acid
17e and derived with the other two derived from acetic 17e and
triuoropropionic acid derived 16g displayed excellent broad
spectrum cytotoxicity. Analysis of the structure activity rela-
tionship data suggested the presence of a bulky moiety origi-
nating from the isocyanide (cyclohexyl and benzyl) enhanced
cytotoxicity. Removal of the acetylenic H-atom was detrimental
to cytotoxicity. The acetylene H-atom retention was conrmed
with the synthesis of Yamada's lead 1 and three additional
analogues 19–21,30 which were the most active analogues
produced with an average GI50 of #1 mM across the cancer cell
lines evaluated. Removal and repositioning of the N-(3,5-dime-
thoxyphenyl) moieties of 1 retained cancer cell line activity
while reducing cytotoxicity against the MCF10A normal cell
line. While these analogues display no greater cytotoxicity
relative to those reported by Yamada,36 they aid in the devel-
opment of a PCMA cytotoxicity pharmacophore. Combined
these data suggest that analogues 19–21, in particular, are
interesting potential anti-cancer development leads.
All cell lines were cultured in a humidied atmosphere 5% CO2
at 37 C. The cancer cell lines were maintained in Dulbecco's
ꢀ
modied Eagle's medium (DMEM) (Trace Biosciences, Aus-
tralia) supplemented with 10% foetal bovine serum, 10 mM
sodium bicarbonate penicillin (100 IU mLꢃ1), streptomycin (100
mg mLꢃ1), and glutamine (4 mM). The non-cancer MCF10A cell
line was cultured in DMEM : F12 (1 : 1) cell culture media, 5%
heat inactivated horse serum, supplemented with penicillin (50
IU mLꢃ1), streptomycin (50 mg mLꢃ1), 20 mM Hepes, L-gluta-
mine (2 mM), epidermal growth factor (20 ng mLꢃ1), hydro-
cortisone (500 ng mLꢃ1), cholera toxin (100 ng mLꢃ1), and
insulin (10 mg mLꢃ1). Cytotoxicity was determined by plating
cells in duplicate in 100 mL medium at a density of 2500–4000
cells per well in 96 well plates. On day 0, (24 h aer plating)
when the cells were in logarithmic growth, 100 mL medium with
or without the test agent was added to each well. Aer 72 h
compound exposure growth inhibitory effects were evaluated
using
the
MTT
(3-[4,5-dimethyltiazol-2-yl]-2,5-
diphenyltetrazolium bromide) assay and absorbance read at
540 nm. An eight point dose response curve was produced from
which the GI50 value was calculated, representing the drug
concentration at which cell growth was inhibited by 50% based
on the difference between the optical density values on day
0 and those at the end of drug exposure.40
Experimental
Chemistry
General Methods. All reagents were purchased from Sigma-
Aldrich, AK Scientic, Matrix Scientic or Lancaster Synthesis
and were used without purication. All solvents were re-distilled
from glass prior to use.
Synthesis of a-amino amides
1H and 13C NMR spectra were recorded on a Bruker
(RS)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenyl-
Advance™ AMX 400 at 400.13 and 100.62 MHz, respectively and propiolamide (12)
Advance™ AMX 600 at 600.21 and 150.92 MHz, respectively.
Method A (batch reaction and using MeOH). A solution of
Chemical shis (d) are reported in parts per million (ppm) MeOH (5.0 mL), aniline (0.09 mL, 1.00 mmol), and benzalde-
measured relative to the internal standards. Coupling constants hyde (0.10 mL, 1.00 mmol) was stirred at room temperature for
(J) are expressed in hertz (Hz). Mass spectra were recorded on 0.5 h. To the stirred solution was added propiolic acid (0.06 mL,
a Shimadzu LCMS 2010 EV and Agilent 6100 series single 1.00 mmol) followed by the addition of cyclohexyl isocyanide
quadrupole LCMS using
a
mobile phase of 1 : 1 (0.11 mL, 1.00 mmol). The reaction mixture was stirred at room
acetonitrile : H2O with 0.1% formic acid. The University of temperature for 24 h and the resulting precipitate was collected,
Wollongong, Australia, Mass Spectrometry User resource & washed with diethyl ether, and dried to afford (12) as a white
Research Facility (MSURRF) analysed samples for High Reso- solid without purication (0.20 g, 55%).
lution Mass Spectrometry HRMS Analytical HPLC traces were
Method B (microwave reaction and using MeOH). A solution of
obtained using a Shimadzu system possessing a SIL-20A auto- MeOH (3.0 mL), aniline (0.09 mL, 1.00 mmol), and benzalde-
sampler, dual LC-20AP pumps, CBM-20A bus module, CTO- hyde (0.10 mL g, 1.00 mmol) was stirred at room temperature
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for 5 min at room temperature. Then, propiolic acid (0.06 mL,
1.00 mmol) followed by the addition of cyclohexyl isocyanide
(0.11 mL, 1.00 mmol) were added to the stirred solution. The
microwave irradiation was applied for 20 min under 120 ꢀC.
Aer 20 minutes the formation of a precipitate was observed,
the solid was collected and washed with diethyl ether and dried
to obtain the desired compound as a white solid (0.30 g, 83%).
Method C (microwave reaction and using [EAN][HNO3]). A
solution of [EAN][HNO3] (3.0 mL), aniline (0.09 mL, 1.00 mmol),
and benzaldehyde (0.10 mL, 1.00 mmol) was stirred at room
temperature for 5 min at room temperature. Then propiolic acid
and cyclohexylcyanide were added sequentially to the stirred
solution and the reaction mixture was then irradiated at 120 ꢀC
for 20 minutes. Following irradiation the reaction mixture was
extracted with EtOAC, washed with H2O and the combined
organic layers dried over MgSO4 and concentrated in vacuo.
Finally, the crude reaction mixture was subjected to ash silica
gel column chromatography (Hexane : EtOAc) to afford pure
product (12) (0.21 g, 58%); LRMS (ESI+) m/z 361 [M + H]+; mp
194.1–196.7; IR (cmꢃ1): 3278, 2924, 2848, 2113, 1640, 1594,
1563, 1491, 1452, 1359, 1308, 1250, 1106, 762, 730, 649, 660,
(RS)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylbut-
2-enamide (16d). Synthesised using the general procedure
(Method b and c) as described for (12) above from aniline (0.09 g,
1.00 mmol), benzaldehyde (0.10 mL, 1.00 mmol), 2-butynoic acid
(0.23 g, 1.00 mmol), and cyclohexyl isocyanide (0.11 mL, 1.00
mmol) in MeOH (5.0 mL) to afford (16d) as a white solid (Method
b 78% and c 56%); LRMS (ESI+) m/z 375 [M + H]+; mp 211.5–213.5;
IR (cmꢃ1): 3266, 2925, 2854, 2256, 1649, 1633, 1553, 1493, 1358,
1249, 1101, 979, 697, 661, 570. 1H NMR (400 MHz, CDCl3): d 7.12–
7.23 (m, 10H), 5.97–6.03 (s, 1H), 5.63–5.72 (d, J ¼ 8.2 Hz, 1H), 3.74–
3.88 (m, 1H), 1.90–1.98 (dd, J ¼ 12.8, 4.2 Hz, 1H), 1.80–1.89 (m,
1H), 1.65–1.70 (d, J ¼ 7.3 Hz, 7H), 1.26–1.41 (m, 2H), 0.97–1.19 (m,
3H); 13C NMR (101 MHz, CDCl3): d 168.1, 155.2, 139.9, 134.3, 130.7,
130.3, 128.6, 128.5, 128.4, 128.2, 91.5, 74.1, 65.1, 48.9, 32.9, 32.9,
25.6, 24.9, 24.8, 4.0.
(RS)-N-Cyclohexyl-2-phenyl-2-(N-phenylacetamido)acetamide
(16e). Synthesised using the general procedure (Method b and c)
as described for (12) from aniline (0.09 mL, 1.00 mmol), benz-
aldehyde (0.10 g, 1.00 mmol), acetic acid (0.23 g, 1.00 mmol), and
cyclohexyl isocyanide (0.11 mL, 1.00 mmol) to afford (16e) as
a white solid (Method b 73%, and c 51%); LRMS (ESI+) m/z 351 [M
+ H]+; mp 186.1–189.4; 3260, 2926, 2848, 1645, 1563, 1493, 1382,
1250, 1240, 889, 730, 696, 647, 548, 515. 1H NMR (400 MHz,
CDCl3): d 7.06–7.25 (m, 10H), 5.99–6.03 (s, 1H), 5.56–5.64 (d, J ¼
7.8 Hz, 1H), 3.70–3.93 (m, 1H), 1.89–1.9945 (m, 1H), 1.84–1.88 (s,
3H), 1.75 (s, 1H), 1.52–1.71 (m, 3H), 1.25–1.41 (m, 2H), 0.96–1.18
(m, 3H); 13C NMR (101 MHz, CDCl3): d 171.3, 168.9, 140.9, 134.9,
130.4, 129.0, 128.4, 128.1, 65.2, 48.9, 33.0, 32.9, 25.6, 25.0, 24.9,
23.4.
1
569. H NMR (400 MHz, CDCl3): d 7.10–7.25 (m, 10H), 6.01 (s,
1H), 5.58 (d, J ¼ 8.2 Hz, 1H), 3.79–3.87 (m, 1H), 2.79 (s, 1H),
1.80–1.98 (m, 1H), 1.79–1.88 (m, 1H), 1.52–1.71 (m, 3H), 1.25–
1.40 (m, 2H), 0.96–1.18 (m, 3H); 13C NMR (101 MHz, CDCl3):
d 167.7, 153.9, 139.2, 133.9, 130.9, 130.5, 128.9, 128.6, 80.7, 76.2,
65.2, 49.0, 32.9, 25.6, 24.9.
(RS)-N-Cyclohexyl-2-(2-methoxy-N-phenylacetamido)-2-phenyl-
acetamide (16b). Synthesised using the general procedure (Method
b and c) as described for (12) by using aniline (0.09 mL, 1.00
mmol), benzaldehyde (0.10 g, 1.00 mmol), methoxyacetic acid
(0.07 g, 1.00 mmol), and cyclohexyl isocyanide (0.11 mL, 1.00
mmol), to afford (16b) as a brown solid (Method b 76% and 66% c);
LRMS (ESI+) m/z 381 [M + H]+; mp 210.1–214.3; IR (cmꢃ1): 3260,
3099, 2926, 2854, 1670, 1645, 1595, 1564, 1493, 1447, 1278, 1250,
(RS)-2-Cyano-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-
phenylacetamide (16f). Synthesised using the general procedure
(Method b and c) as described for (12) from aniline (0.09 mL,
1.00 mmol), benzaldehyde (0.10 g, 1.00 mmol), cyanoacetic acid
(0.23 g, 1.00 mmol), and cyclohexyl isocyanide (0.11 mL, 1.00
mmol), to afford (16f) as a white solid (Method b 60% and c
45%); LRMS (ESI+) m/z 376 [M + H]+; mp 241.9–245.4; IR (cmꢃ1):
3253, 2928, 2858, 1668, 1643, 1594, 1563, 1493, 1386, 1239,
1
1127, 976, 698, 557. H NMR (400 MHz, CDCl3): d 7.07–7.30 (m,
10H), 6.05 (s, 1H), 5.58–5.63 (d, J ¼ 8.0 Hz, 1H), 3.67–3.88 (m, 3H),
3.33 (s, 3H), 1.90–2.00 (m, 1H), 1.80–1.90 (d, J ¼ 12.5 Hz, 1H), 1.24–
1.41 (q, J ¼ 11.6 Hz, 2H), 0.96–1.19 (m, 3H); 13C NMR (101 MHz,
CDCl3): d 169.9, 168.5, 138.5, 134.4, 130.6, 130.6, 129.1, 128.6,
128.5, 71.0, 65.1, 59.4, 49.0, 33.0, 32.9, 25.6, 25.0, 24.9.
1
1104, 1005, 734, 697, 408. H NMR (400 MHz, CDCl3): d 7.05–
7.31 (m, 10H), 5.99–6.02 (s, 1H), 5.38–5.44 (d, J ¼ 8.1 Hz, 1H),
3.75–3.87 (m, 1H), 3.1281–3.2897 (m, 2H), 1.89–1.99 (dd, J ¼
12.0, 4.1 Hz, 1H), 1.77–1.88 (m, 1H), 1.6245–1.71 (m, 2H), 1.23–
1.42 (m, 3H), 0.93–1.17 (m, 3H); 13C NMR (101 MHz, CDCl3):
d 167.9, 162.7, 138.6, 133.8, 130.5, 129.3, 129.1, 128.8, 65.8, 49.2,
33.0, 32.9, 26.4, 25.6, 25.0, 24.9.
(RS)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-3,3,3-tri-
uoro-N-phenylpropanamide (16g). Synthesised using the
general procedure (Method b and c) as described for (12) from
aniline (0.09 mL, 1.00 mmol), benzaldehyde (0.10 g, 1.00
mmol), 3,3,3-triuoropropionic acid (0.23 g, 1.00 mmol), and
cyclohexyl isocyanide (0.11 mL, 1.00 mmol) to afford (16g) as
a white solid (Method b 45% and c 36%); LRMS (ESI+) m/z 377
[M + H]+; mp 202.9–211.9; IR (cmꢃ1): 3327 (NH), 3056 (CH),
2961, 2929 (CH); 1H NMR (400 MHz, CDCl3): d 6.95–7.46 (m,
10H), 6.03 (s, 1H), 5.46–5.56 (d, J ¼ 8.1 Hz, 1H), 3.74–3.86 (m,
1H), 2.83–3.02 (m, 2H), 1.89–1.98 (dd, J ¼ 13.3, 4.3 Hz, 2H),
1.79–1.88 (m, 1H), 1.52–1.72 (m, 3H), 1.40–1.47 (d, J ¼ 9.1 Hz,
(RS)-(E)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenyl-
but-2-enamide (16c). Synthesised using the general procedure
(Method b and c) as described for (12) above from aniline (0.09 mL,
1.00 mmol), benzaldehyde (0.10 mL, 1.00 mmol), crotonic acid
(0.23 g, 1.00 mmol), and cyclohexyl isocyanide (0.11 mL, 1.00
mmol), to afford (16c) as a white solid (Method b 65% and c 49%);
LRMS (ESI+) m/z 377 [M + H]+, mp 172.5–187.4; IR (cmꢃ1): 3266,
2926, 2848, 1666, 1645, 1627, 1447, 1367, 1237, 1107, 960, 750, 697,
558. 1H NMR (400 MHz, CDCl3): d 7.02–7.24 (m, 10H), 6.90–7.02 (m,
1H), 6.03 (s, 1H), 5.74–5.84 (d, J ¼ 8.0 Hz, 1H), 5.57–5.65 (dd, J ¼
15.0, 1.7 Hz, 1H), 3.77–3.89 (m, 1H), 1.90–1.99 (m, 1H), 1.81–1.90
(m, 1H), 1.52–1.73 (m, 5H), 1.24–1.41 (m, 3H), 0.97–1.20 (m, 3H); 13
C
NMR (101 MHz, CDCl3): d 168.7, 166.5, 142.3, 140.0, 134.9, 130.5,
130.2, 128.8, 128.3, 128.2, 127.9, 122.9, 65.6, 48.6, 32.9, 32.8, 25.5,
24.8, 24.7, 18.0.
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1H), 1.24–1.40 (m, 2H), 0.93–1.17 (m, 3H). 13C NMR (101 MHz,
CDCl3) d 168.2, 164.1, 164.1, 139.0, 134.1, 130.5, 128.9, 128.8,
128.6, 65.3, 49.0, 39.5, 39.2, 38.9, 38.6, 32.9, 32.9, 25.6, 24.1,
24.9.
(RS)-N-Benzyl-2-phenyl-2-(N-phenylacetamido)acetamide (17e).
Synthesised using the general procedure (Method b and c) as
described for (12) from aniline (0.09 mL, 1.00 mmol), benzalde-
hyde (0.10 g, 1.00 mmol), acetic acid (0.23 g, 1.00 mmol), and
benzyl isocyanide (0.12 mL, 1.00 mmol), to afford (17e) as a white
solid (Method b 70% and c 41%); LRMS (ESI+) m/z 359 [M + H]+;
mp 185.2–188.7; IR (cmꢃ1): 3247 (NH), 1652, 1645 (CO); 1H NMR
(400 MHz, CDCl3): d 1.65–1.69 (s, 1H), 1.85–1.88 (s, 3H), 4.43–4.55
(m, 2H), 6.03–6.12 (d, J ¼ 10.4 Hz, 2H), 7.06–7.32 (m, 15H); 13C
NMR (101 MHz, CDCl3): d 171.4, 169.9, 140.9, 138.2, 134.6, 130.5,
130.4, 129.1, 128.8, 128.6, 128.5, 128.2, 127.7, 127.5, 65.4, 43.9,
23.4.
(RS)-N-Benzyl-2-(2-cyano-N-phenylacetamido)-2-phenylacet-
amide (17f). Synthesised utilising the general procedure
described in (12) from aniline (0.09 mL, 1.00 mmol), benzal-
dehyde (0.10 g, 1.00 mmol), cyanoacetic acid (0.23 g, 1.00
mmol), and benzyl isocyanide (0.12 mL, 1.00 mmol), to afford
(17f) as a brown solid (Method b 79% and c 61%); LRMS (ESI+)
m/z 389 [M + H]+; mp 216.1–221.1; IR (cmꢃ1): 3256 (NH), 1664,
1654 (CO); 1H NMR (400 MHz, CDCl3): d 3.15–3.29 (m, 2H),
4.41–4.55 (m, 2H), 5.91 (s, 1H), 6.05 (s, 1H), 7.08–7.29 (m, 15H);
13C NMR (101 MHz, CDCl3): d 168.9, 162.8, 138.6, 137.8, 130.6,
129.3, 129.2, 128.8, 128.8, 127.7, 127.7, 114.1, 65.9, 44.1, 26.5.
(RS)-N-(2-(Benzylamino)-2-oxo-1-phenylethyl)-3,3,3-triuoro-
N-phenylpropanamide (17g). Synthesised using the general
procedure (Method b and c) as described for (12) from aniline
(0.09 mL, 1.00 mmol), benzaldehyde (0.10 g, 1.00 mmol), 3,3,3-
triuoropropionic acid (0.23 g, 1.00 mmol), and benzyl iso-
cyanide (0.12 mL, 1.00 mmol), to afford (17g) as a white solid
(Method b 41% and c 30%); LRMS (ESI+) m/z 427 [M + H]+, mp
160.8–164.4; IR (cmꢃ1): 3266 (NH), 1666, 1654 (CO); 1H NMR
(400 MHz, CDCl3): d 7.54–7.79 (s, 1H), 7.14–7.31 (m, 11H), 7.09–
7.13 (m, 2H), 6.42–6.68 (s, 1H), 6.06–6.10 (s, 1H), 5.93–6.00 (s,
1H), 4.38–4.58 (m, 2H), 2.82–3.06 (m, 2H); 13C NMR (101 MHz,
CDCl3): d 169.0, 133.6, 130.4, 128.9, 128.7, 128.6, 127.6, 127.5,
95.0, 65.3, 43.9.
(RS)-Ethyl (2-phenyl-2-(N-phenylpropiolamido)acetyl)glycinate
(18a). Synthesised using the general procedure (Method b and c) as
described for (12) above from aniline (0.09 mL, 1.00 mmol),
benzaldehyde (0.10 g, 1.00 mmol), propiolic acid (0.06 g, 1.00
mmol), and ethyl isocyanoacetate (0.11 mL, 1.00 mmol), to afford
(18a) as a white solid (Method b 71% and c 60%); LRMS (ESI+) m/z
365 [M + H]+; mp 170.5–172.2; IR (cmꢃ1): 3333 (NH), 1625 (CO); 1H
NMR (400 MHz, CDCl3): d 7.12–7.25 (m, 10H), 6.31–6.36 (s, 1H),
6.11–6.15 (s, 1H), 4.13–4.20 (q, J ¼ 7.1 Hz, 2H), 4.02–4.06 (t, J ¼
5.1 Hz, 2H), 2.77–2.82 (s, 1H), 2.01–2.03 (s, 1H), 1.22–1.26 (t, J ¼
7.1 Hz, 4H). 13C NMR (101 MHz, CDCl3): d 169.6, 168.9, 153.9,
139.0, 133.2, 130.8, 130.6, 129.0, 128.7, 128.7, 128.6, 80.8, 76.1,
64.9, 61.6, 60.5, 41.8, 21.1, 14.2.
(RS)-Ethyl (2-(2-methoxy-N-phenylacetamido)-2-phenylacetyl)
glycinate (18b). Synthesised using the general procedure
(Method B and C) as described for (12) from aniline (0.09 mL,
1.00 mmol), benzaldehyde (0.10 mL, 1.00 mmol), methoxyacetic
acid (0.08 mL, 1.00 mmol), and ethyl isocyanoacetate (0.12 mL,
1.00 mmol), to afford (18b) as a white solid (Method B 0.29, 75%
and Method C 0.25 g, 65%); LRMS (ESI+) m/z 385 [M + H]+; mp
(RS)-N-(2-(Benzylamino)-2-oxo-1-phenylethyl)-N-phenylprop-
iolamide (17a). Synthesised using the general procedure
(Method b and c) as described for (12) from aniline (0.09 mL,
1.00 mmol), benzaldehyde (0.10 g, 1.00 mmol), propiolic acid
(0.06 g, 1.00 mmol), and benzyl isocyanide (0.12 mL, 1.00
mmol), to afford (17a) as a white solid (Method b 70% and c
54%); LRMS (ESI+) m/z 369 [M + H]+, mp 184.1–194.9; IR (cmꢃ1):
3307 (NH), 3189, 1668, 1635 (C); 1H NMR (400 MHz, CDCl3):
d 7.12–7.32 (m, 15H), 6.03–6.05 (s, 1H), 5.97–6.03 (d, J ¼ 6.1 Hz,
1H), 4.44–4.56 (m, 2H), 3.45–3.49 (s, 1H); 13C NMR (101 MHz,
CDCl3): d 168.7, 153.9, 139.2, 137.9, 133.5, 130.9, 130.5, 128.8,
128.7, 128.7, 127.7, 127.6, 80.8, 65.4, 51.0, 44.0.
(RS)-N-Benzyl-2-(2-methoxy-N-phenylacetamido)-2-phenyl-
acetamide (17b). Synthesised using the general procedure
(Method b and c) as described for (12) from aniline (0.09 mL,
1.00 mmol), benzaldehyde (0.10 g, 1.00 mmol), methoxyacetic
acid (0.07 mL, 1.00 mmol), and benzyl isocyanide (0.12 mL, 1.00
mmol) to afford (17b) as a white solid (Method b 67% and c
69%); LRMS (ESI+) m/z 389 [M + H]+. Mp 182.5–185.7; IR (cmꢃ1):
3255 (NH), 1664, 1651 (CO); 1H NMR (400 MHz, CDCl3): d 7.07–
7.33 (m, 15H), 6.62–6.68 (m, 1H), 6.09 (s, 1H), 4.46–4.52 (dd, J ¼
8.6, 5.8 Hz, 1H), 3.68–3.81 (d, J ¼ 1.6 Hz, 2H), 3.42 (s, 1H), 3.34
(s, 2H); 13C NMR (101 MHz, CDCl3): d 170.0, 169.5, 138.4, 138.1,
133.9, 130.6, 130.5, 129.6, 129.2, 129.1, 128.8, 128.8, 128.7,
128.7, 128.6, 128.1, 127.7, 127.5, 119.7, 113.9, 71.0, 65.3, 59.4,
44.0.
(RS)-(E)-N-(2-(Benzylamino)-2-oxo-1-phenylethyl)-N-phenylbut-
2-enamide (17c). Synthesised using the general procedure (Method
b and c) as described for (12) from aniline (0.09 mL, 1.00 mmol),
benzaldehyde (0.10 g, 1.00 mmol), crotonic acid (0.23 g, 1.00
mmol), and benzyl isocyanide (0.12 mL, 1.00 mmol), to afford (17c)
as a white solid (Method b 71% and c 51%); LRMS (ESI+) m/z 385
[M + H]+; mp 208.9–221.7; IR (cmꢃ1): 3337 (NH), 1657, 1620 (CO);
1H NMR (400 MHz, CDCl3): d 7.03–7.31 (m, 15H), 6.92–7.03 (m,
1H), 6.25 (s, 1H), 6.08 (s, 1H), 5.59–5.66 (dd, J ¼ 15.1, 1.7 Hz, 1H),
4.48–4.54 (d, J ¼ 5.8 Hz, 2H), 1.68–1.74 (dd, J ¼ 7.0, 1.7 Hz, 3H); 13
C
NMR (101 MHz, CDCl3): d 169.9, 166.7, 142.6, 140.1, 138.3, 134.7,
130.6, 130.4, 129.0, 128.7, 128.5, 128.5, 128.1, 127.7, 127.4, 123.0,
66.0, 43.9, 18.2.
(RS)-N-(2-(Benzylamino)-2-oxo-1-phenylethyl)-N-phenylbut-
2-ynamide (17d). Synthesised using the general procedure
(Method b and c) as described for (12) above from aniline (0.09
mL, 1.00 mmol), benzaldehyde (0.10 g, 1.00 mmol), 2-butynoic
acid (0.23 g, 1.00 mmol), and benzyl isocyanide (0.12 mL, 1.00
mmol), to afford (17d) as a white solid (Method b 67% and c
55%); LRMS (ESI+) m/z 383 [M + H]+; mp 183.1–187.8; IR (cmꢃ1):
1
3298 (NH), 2249, 1164, 1629 (CO); H NMR (400 MHz, CDCl3):
d 7.26–7.30 (m, 2H), 7.16–7.25 (m, 13H), 6.07–6.12 (d, J ¼ 6.1 Hz,
1H), 6.03 (s, 1H), 4.34–4.63 (m, 3H), 1.67 (s, 3H); 13C NMR (101
MHz, CDCl3): d 169.1, 155.2, 139.9, 138.0, 134.0, 130.7, 130.4,
128.8, 128.8, 128.6, 128.5, 128.3, 127.7, 127.5, 91.6, 74.1, 65.4,
44.0, 4.0.
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170–178 ꢀC; IR (cmꢃ1): 3330 (NH), 1627 (CO); 1H NMR (400 MHz, 13C NMR (101 MHz, CDCl3): d 169.6, 169.1, 162.9, 138.5, 133.0, 130.8,
CDCl3) d 7.26–7.13 (m, 10H), 6.43–6.40 (m, 1H), 6.18 (s, 1H), 4.12 130.4, 129.4, 129.2, 128.8, 114.0, 65.6, 61.7, 41.8, 26.4, 14.2.
(q, J ¼ 7.2 Hz, 2H), 4.00 (t, J ¼ 5.5 Hz, 2H), 3.69 (s, 2H), 3.27 (s,
(RS)-Ethyl (2-phenyl-2-(3,3,3-triuoro-N-phenylpropanamido)
3H), 1.20 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 169.9, acetyl)glycinate (18g). Synthesised using the general procedure
169.7, 169.6, 138.1, 133.6, 130.6, 130.4, 129.0, 128.6, 128.6, 128.3, (Method b and c) as described for (12) from aniline (0.09 mL, 1.00
70.8, 64.6, 61.3, 59.2, 41.6, 14.1.
mmol), benzaldehyde (0.10 g, 1.00 mmol), 3,3,3-tri-
(RS)-(E)-Ethyl 2-(2-phenyl-2-(N-phenylbut-2-enamido)acetamido) uoropropionic acid (0.23 g, 1.00 mmol), and ethyl iso-
acetate (18c). Synthesised using the general procedure (Method cyanoacetate (0.11 mL, 1.00 mmol), to afford (18g) as a white
b and c) as described for (12) from aniline (0.09 g, 1.00 mmol), solid (Method b 50% and c 45%); LRMS (ESI+) m/z 423 [M + H]+,
benzaldehyde (0.10 g, 1.00 mmol), crotonic acid (0.23 g, 1.00 mmol), mp 164.2–166.5. IR (cmꢃ1): 3393 (NH), 2206 (CN) 1660, 1624
1
and ethyl isocyanoacetate (0.11 mL, 1.00 mmol), to afford (18c) as (CO); H NMR (400 MHz, CDCl3): d 7.56–7.74 (s, 1H), 7.02–7.42
a white solid (Method b 68% and c 51%); LRMS (ESI+) m/z 381 [M + (m, 9H), 6.46–6.64 (d, J ¼ 7.1 Hz, 1H), 6.19–6.25 (s, 1H), 6.12–6.16
1
H]+, mp 181.9–187.2; IR (cmꢃ1): 3331 (NH), 1662, 1625 (CO); H (s, 1H), 4.13–4.21 (q, J ¼ 7.1 Hz, 2H), 4.03–4.08 (dd, J ¼ 5.3, 2.7 Hz,
NMR (400 MHz, CDCl3) d 7.15–7.25 (m, 9H), 6.91–7.02 (dd, J ¼ 15.0, 2H), 2.83–3.03 (qd, J ¼ 10.0, 7.9 Hz, 2H), 1.21–1.27 (t, J ¼ 7.1 Hz,
6.9 Hz, 2H), 6.54–6.59 (s, 1H), 6.10–6.14 (s, 1H), 5.58–5.66 (dd, J ¼ 3H). 13C NMR (101 MHz, CDCl3): d 169.6, 169.3, 164.2, 164.2,
15.1, 1.7 Hz, 1H), 4.14–4.21 (q, J ¼ 7.2 Hz, 2H), 4.05–4.09 (dd, J ¼ 5.3, 138.9, 133.4, 130.7, 130.5, 129.0, 128.7, 65.2, 61.7, 41.8, 39.5, 39.2,
3.2 Hz, 2H), 1.67–1.72 (dd, J ¼ 7.0, 1.7 Hz, 3H), 1.22–1.27 (t, J ¼ 38.9, 38.6, 14.2.
7.1 Hz, 4H); 13C NMR (101 MHz, CDCl3) d 170.0, 169.8, 166.7, 142.8,
(RS)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(4-methox-
140.0, 134.3, 134.2, 130.5, 130.4, 129.0, 128.5, 128.4, 128.1, 122.8, yphenyl)propiolamide (19). Synthesised using the general proce-
115.4, 65.7, 61.5, 41.7, 18.2, 14.2. dure (method a) from 4-methoxybenzaldehyde (0.136 g, 1.00
(RS)-Ethyl (2-phenyl-2-(N-phenylbut-2-ynamido)acetyl)glycinate mmol), 2-butynoic acid (0.23 g, 1.00 mmol), aniline (0.9 mL, 1.00
(18d). Synthesised using the general procedure (Method b and c) mmol) and cyclohexyl isocyanide (0.11 mL, 1.00 mmol) to afford
as described for (12) from aniline (0.09 mL, 1.00 mmol), benzal- (19) as a white solid (0.259 g, 66%) LRMS m/z 391 [M + H]+ mp:
1
dehyde (0.10 g, 1.00 mmol), 2-butynoic acid (0.23 g, 1.00 mmol), 169–172; H NMR (400 MHz, CDCl3) d 7.24–7.20 (m, 3H, signal
and ethyl isocyanoacetate (0.11 mL, 1.00 mmol), to afford (18b) as overlaps residual CHCl3), 7.17–7.16 (m, 2H), 7.09 (t, J ¼ 8.1 Hz, 1H),
a white solid (Method b 66% and c 54%); LRMS (ESI+) m/z 379 [M + 6.79 (dd, J ¼ 8.2, 2.2 Hz, 2H), 6.74 (bs s, 1H), 5.96 (s, 1H), 5.53 (d, J
H]+; mp 175.6–178.4; IR (cmꢃ1): 3337 (NH), 1657, 1620 (CO), 1594, ¼ 7.7 Hz, 1H), 3.87–3.78 (m, 1H), 3.66, s, 3H), 2.82 (s, 1H) 1.89 (dd,
1549; 1H NMR (400 MHz, CDCl3): d 7.11–7.24 (m, 11H), 6.35 (s, 1H), J ¼ 34.5, 10.4 Hz, 2H), 1.68–1.56 (m, 3H, signal overlaps residual
6.11 (s, 1H), 4.14–4.22 (q, J ¼ 7.1 Hz, 2H), 4.03–4.10 (d, J ¼ 5.3 Hz, water), 1.40–1.28 (m, 2H), 1.17–0.98 (m, 3H); 13C NMR (101 MHz,
2H), 1.63–1.70 (s, 3H), 1.22–1.29 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 CDCl3) d 167.7, 159.7, 153.8, 140.3, 134.0, 130.4 (2C), 129.2, 128.9,
MHz, CDCl3): d 169.6, 169.3, 155.2, 139.7, 133.6, 130.6, 130.5, 128.7 (2C), 123.2, 115.8, 115.1, 80.5, 76.2, 65.4, 55.5, 49.0, 32.95,
128.8, 128.5, 128.5, 128.3, 91.7, 74.0, 64.9, 61.6, 60.5, 41.8, 21.1, 32.90, 25.6, 24.9, 24.8.
14.3, 14.2, 4.0.
(RS)-N-(2-(Cyclohexylamino)-1-(2,3-dimethoxyphenyl)-2-oxo-
(RS)-Ethyl (2-(2-methoxy-N-phenylacetamido)-2-phenylacetyl) ethyl)-N-phenylpropiolamide (20). Synthesised by method A
glycinate (18e). Synthesised using the general procedure from 2,3-dimethoxybenzaldehyde (0.166 g, 1.00 mmol), 2-buty-
(Method b and c) as described for (12) from aniline (0.09 g, 1.00 noic acid (0.23 g, 1.00 mmol), aniline (0.9 mL, 1.00 mmol) and
mmol), benzaldehyde (0.10 g, 1.00 mmol), acetic acid (0.23 g, 2.70 cyclohexyl isocyanide (0.11 mL, 1.00 mmol) to afford (20) as
mmol), and ethyl isocyanoacetate (0.11 mL, 1.00 mmol), to afford a white solid (0.2682 g, 64%). LRMS m/z 421.2 [M + H]+ mp 224
(18e) as a white solid (Method b 66% and c 69%); LRMS (ESI+) m/z (dec); 1H NMR (400 MHz, CDCl3) d 7.24–7.17 (m, 5H), 6.82–6.74
355 [M + H]+, mp 183.6–186.1. IR (cmꢃ1): 3244, 3085, 3061, 1655; (m, 2H), 6.59 (dd, J ¼ 7.4, 1.4 Hz, 1H), 6.40 (s, 1H), 5.49 (d, J ¼
1H NMR (400 MHz, CDCl3): d 6.97–7.18 (m, 10H), 6.59–6.65 (t, J ¼ 7.5 Hz, 1H), 3.84–3.77 (m, 7H), 2.78 (s, 1H), 1.89 (dd, J ¼ 38.5,
5.4 Hz, 1H), 6.11–6.15 (s, 1H), 4.06–4.14 (q, J ¼ 7.1 Hz, 2H), 3.95– 10.8 Hz, 2H), 1.70–1.55 (m, 3H, signal overlaps residual water),
4.01 (dd, J ¼ 6.6, 5.4 Hz, 2H), 1.76–1.79 (s, 3H), 1.15–1.21 (t, J ¼ 1.40–1.27 (m, 2H), 1.16–0.97 (m, 3H); 13C NMR (101 MHz,
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): d 171.2, 170.0, 169.6, CDCl3) d 168.1, 153.8, 152.5, 147.9, 139.5, 130. 7 (2C), 128.59,
140.5, 134.2, 130.5, 130.2, 128.8, 128.3, 128.2, 128.0, 64.6, 61.3, 128.56 (2C), 127.8, 123.7, 122.8, 113.2, 80.4, 76.4, 61.1, 58.8,
41.5, 23.1, 14.1.
55.9, 49.0, 33.0, 32.90, 25.6, 25.0, 24.9.
(RS)-Ethyl 2-(2-(2-cyano-N-phenylacetamido)-2-phenylacetamido)
(RS)-N-(2-(Cyclohexylamino)-1-(3,4-dimethoxyphenyl)-2-oxo-
acetate (18f). Synthesised using the general procedure (Method ethyl)-N-phenylpropiolamide (21). Synthesised by method A
b and c) as described for (12) from aniline (0.09 mL, 1.00 mmol), from 2,3-dimethoxybenzaldehyde (0.166 g, 1.00 mmol), 2-buty-
benzaldehyde (0.10 g, 1.00 mmol), cyanoacetic acid (0.23 g, 2.70 noic acid (0.23 g, 1.00 mmol), aniline (0.9 mL, 1.00 mmol) and
mmol), and ethyl isocyanoacetate (0.11 mL, 1.00 mmol), to afford cyclohexyl isocyanide (0.11 mL, 1.00 mmol) to afford (21) as
(18f) as a white solid (Method b 58% and c 59%); LRMS (ESI+) m/z a white solid (0.231 g, 55%). LRMS m/z 421.2 [M + H]+ 1H NMR
380 [M + H]+; mp 168.2–172.2. IR (cmꢃ1): 3397 (NH), 2205 (CN) 1660, (400 MHz, CDCl3) d 7.24–7.17 (m, 5H, overlapping signal with
1624 (CO); 1H NMR (400 MHz, CDCl3): d 7.05–7.33 (m, 10H), 6.15– CDCl3), 6.77–6.69 (m, 2H), 6.51 (s, 1H), 6.00 (s, 1H), 5.57 (d, J ¼
6.21 (s, 1H), 6.14 (s, 1H), 4.14–4.21 (q, J ¼ 7.2 Hz, 2H), 4.01–4.10 (dd, 7.6 Hz, 1H), 3.83 (s, 3H) 3.81–3.75 (m, 1H), 3.60 (s, 3H), 2.80 (s,
J ¼ 6.9, 5.3 Hz, 2H), 3.15–3.29 (m, 2H), 1.22–1.28 (t, J ¼ 7.1 Hz, 3H). 1H), 1.88 (dd, J ¼ 48.3, 11.2 Hz, 2H), 1.69–1.56 (m, 3H, over-
lapping signal with residual water), 1.39–1.28 (m, 2H), 1.16–0.98
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