Exploratory applications of 2-nitrobenzaldehyde-derived Morita–Baylis–Hillman adducts as synthons in the construction of drug-like scaffolds

Article abstract of DOI:10.1080/00397911.2018.1559333

Morita–Baylis–Hillman adducts, prepared from 2-nitrobenzaldehyde precursors and either methyl acrylate or methyl vinyl ketone, have been used as critical synthons in the preparation of α-[(alkylamino)methyl]cinnamate esters and their but-3-en-2-one analogs, cinnamate ester-azidothymidine (AZT) conjugates, 2-quinolone and quinoline derivatives. Computer docking studies have been conducted to explore the potential of the cinnamate ester–AZT conjugates as potential dual-action HIV-1 integrase–reverse transcriptase (IN–RT) inhibitors. The results further demonstrate the applicability of Morita–Baylis–Hillman methodology in the construction of complex drug-like scaffolds.

Full text of DOI:10.1080/00397911.2018.1559333

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Exploratory applications of 2-nitrobenzaldehyde-
derived Morita–Baylis–Hillman adducts as
synthons in the construction of drug-like scaffolds
Kenudi C. Idahosa, Michael T. Davies-Coleman & Perry T. Kaye
To cite this article: Kenudi C. Idahosa, Michael T. Davies-Coleman & Perry T. Kaye (2019):
Exploratory applications of 2-nitrobenzaldehyde-derived Morita–Baylis–Hillman adducts
as synthons in the construction of drug-like scaffolds, Synthetic Communications, DOI:
10.1080/00397911.2018.1559333
To link to this article: https://doi.org/10.1080/00397911.2018.1559333
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1559333
Exploratory applications of 2-nitrobenzaldehyde-derived
Morita–Baylis–Hillman adducts as synthons in the
construction of drug-like scaffolds
Kenudi C. Idahosa, Michael T. Davies-Coleman, and Perry T. Kaye
Department of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes University,
Grahamstown, South Africa
ABSTRACT
ARTICLE HISTORY
Received 21 May 2018
Morita–Baylis–Hillman adducts, prepared from 2-nitrobenzaldehyde
precursors and either methyl acrylate or methyl vinyl ketone, have
been used as critical synthons in the preparation of a-[(alkylamino)-
methyl]cinnamate esters and their but-3-en-2-one analogs, cinna-
mate ester-azidothymidine (AZT) conjugates, 2-quinolone and
quinoline derivatives. Computer docking studies have been con-
ducted to explore the potential of the cinnamate ester–AZT conju-
gates as potential dual-action HIV-1 integrase–reverse transcriptase
(IN–RT) inhibitors. The results further demonstrate the applicability of
Morita–Baylis–Hillman methodology in the construction of complex
drug-like scaffolds.
KEYWORDS
Antimalarial; azidothymidine
(AZT); dual-action drugs;
HIV-1 integrase–reverse
transcriptase inhibitors;
Morita–Baylis–Hillman reac-
tion; quinoline; quinololone
GRAPHICAL ABSTRACT
2-nitrobenzaldehyde-derived
R1 = OCH3
R1 = CH3
Baylis-Hillman adducts
α
-[(alkylamino)methyl]-
cinnamate esters
2-[(alkylamino)methyl]-
O
OH
R4
R3
3-(2-nitrophenyl)-2-butenones
cinnamate ester - AZT
conjugates
R1
3-[(alkylamino)methyl]-
2-methylquinolines
NO2
3-[(alkylamino)methyl]-
quinolones
R2
Introduction
Malaria and HIV/AIDS present major health challenges, particularly in sub-Saharan
Africa.[1,2] The emergence of resistance to established drugs has compounded the prob-
lems and has led to an avoidance of monotherapies in the treatment of malaria[3] and,
in the treatment of HIV/AIDS, to the introduction of highly active antiretroviral therapy
(HAART), typically involving the use of a combination of HIV-1 protease (PR) and
CONTACT Perry T. Kaye
P.Kaye@ru.ac.za
Department of Chemistry and Centre for Chemico- and Biomedicinal
Research, Lucas Avenue, Rhodes University, Grahamstown 6140, South Africa.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
K. IDAHOSA ET AL.
reverse transcriptase (RT) inhibitors.[4,5] There remains, however, an urgent need for
new and effective medicinal agents to treat these devastating diseases.
R1
OH
Ph
O
O
OH
H
N
R
N
O
O
N
N
R2
N
H
H
N
R
N
O
O
O
Ph
1
2
N
O
O
H
In our own research, attention has been given to the development of novel com-
pounds as potential inhibitors of Plasmodium faciparum DOXP-reductoisomerase
(PfDXR)[6,7] – an established enzyme target for antimalarial intervention.[8] Attention
has also been given to applications of Baylis–Hillman methodology in the construction
of: (i) ritonavir analogs 1,[9] which contain a hydroxyethylene diamine moiety[10] char-
acteristic of the first-generation HIV-1 PR inhibitors; and (ii) coumarin-azidothymidine
(AZT) conjugates 2,[11] as dual HIV-1 PR and reverse transcriptase (RT) inhibitors. The
HIV-1 RT inhibitor AZT[12] was the first drug to be approved for the treatment of
HIV/AIDS infections, while the cinnamate ester moiety is present in certain compounds
which have been found to exhibit HIV-1 integrase inhibition, e.g., caffeic acid phenyl
ester (CAPE) and L-chicoric acid (LCA) and their derivatives.[13–15] In this paper we
report on the exploratory studies outlined in Figure 1, which involve the synthetic elab-
oration of 2-nitrobenzaldehyde-derived Morita–Baylis–Hillman adducts, to access novel
compounds with antimalarial and anti-HIV potential.
Results and discussion
Access to the series of known[16] Baylis–Hillman adducts 5a–h was achieved by reacting
the corresponding 2-nitrobenzaldehydes 3a–h with methyl acrylate 4, using 1,4-diazabic-
cyclo[2.2.2]octane (DABCO) as catalyst and chloroform as a solvent, over periods rang-
ing from 2 d to 6 weeks. Reaction progress was monitored by TLC analysis and, in a
few instances in which a significant amount of the starting material remained, add-
itional methyl acrylate and DABCO were added to promote further reaction. Work-up
and flash chromatography afforded the desired adducts 5a–h in yields ranging from 37
to 91%. Most of the 2-nitrobenzaldehydes (3) were purchased but, due to their cost,
R1 = OCH3
R1 = CH3
2-nitrobenzaldehyde-derived
Baylis-Hillman adducts
α-[(alkylamino)methyl]-
2-[(alkylamino)methyl]-
cinnamate esters
O
OH
R4
R3
3-(2-nitrophenyl)-2-butenones
R1
cinnamate ester - AZT
conjugates
3-[(alkylamino)methyl]-
2-methylquinolines
NO2
3-[(alkylamino)methyl]-
quinolones
R2
Figure 1. Routes to drug-like scaffolds using 2-nitrobenzaldehyde-derived Morita–Baylis–Hillman
adducts (R1¼OMe or Me).

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3
4-chloro-2-nitrobenzaldehyde 3g and 5-methoxy-2-nitrobenzaldehyde 3h (required to
model the aryl substitution patterns in chloroquine and quinine, respectively) were spe-
cially prepared using methods reported by Ahmad et al.[17] (affording 3g; 75%) and by
Xiong et al.[18] (affording 3h; 63–68%).
The secondary amine, piperidine, was initially used to explore conjugate (aza-
Michael) addition to the methyl ester adducts 5a,e in anhydrous THF (Scheme 1).
Solutions containing equimolar concentrations of the reactants were stirred for 2–5 d to
afford the products 6a,e as diastereomeric mixtures in essentially quantitative yields.
Two stereogenic centers are generated (at C2 and C3) in the process, and the presence
1
of diastereomers is indicated by the doubling of H- and 13C NMR signals; integration
1
of relevant H-NMR signals permitted determination of the diastereomeric ratio in each
case. Attempts to separate the diastereomers proved unsuccessful, and the diastereo-
meric mixtures were used in subsequent reactions. Refluxing the diastereomeric mixture
6a with CuCl2 and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC) in toluene
afforded the cinnamate ester derivative 7a as a ca. 3:1 mixture of the E- and Z-diaster-
eomers in disappointing overall yield (15%). Reductive cyclization of the 3-methoxy
analog 6e, using electrolytic iron powder in refluxing acetic acid, afforded the 3-(acetox-
ymethyl)-2-quinolone 8e in a mere 12% yield with acetate having unexpectedly dis-
placed the piperidyl group in the process. However, in a modification of an earlier
protocol,[19] reaction of the methyl ester adduct 5a with the primary amine, 2-amino-5-
diethylaminopentane 9 (present as the 4-alkylamino substituent in chloroquine), proved
to be more encouraging, Flash chromatography of the crude product on basified silica
gel afforded compound 10a as a diastereomeric mixture in excellent overall yield (87%).
This compound contains three stereogenic centers and the presence of diastereomers
was clearly evident in the NMR spectra. Analysis of the relative integrals of the split sig-
1
nals at ca. 3.7 and 5.8 ppm in the H NMR spectrum of compound 10a indicates a dia-
stereomeric ratio of ca. 3:1. Reductive cyclization of the aza-Michael adduct 10a, to
access 2-quinolone derivatives (in which the issue of diastereoselectivity is removed),
was explored using hydrogen and a 10% palladium-on-carbon catalyst in ethanol. Flash
chromatography of the crude products from the reaction (on Discovery DSC-Diol, basi-
fied and conditioned overnight with basic eluent) afforded the desired 3-aminomethyl-
2-quinolone 11a (27%) and, unexpectedly, 1,2-dihydro-3-methylquinoline 12a (14%).
The formation of compound 12a is tentatively attributed to reductive cyclization of the
substrate to afford a 4-hydroxy-3-methylenequinolone intermediate, which undergoes
further reduction and dehydration. (We have recently reported a somewhat different
Morita–Baylis–Hillman approach to 3-benzamido-2-quinolones as potential HIV-1 inte-
grase inhibitors.[20]
)
With a view to accessing 2-nitrocinnamate ester-AZT conjugates as potential
dual-action HIV-1 IN/RT inhibitors, attention was given to the preparation of the inter-
mediate 2-chloromethyl cinnamate esters (13). However, this proved unexpectedly prob-
lematic. Shi et al.,[21] had reported an acceleration of the Morita–Baylis–Hillman
reaction of p-nitrobenzaldehyde with MVK using a combination of a Lewis base, a qua-
ternary ammonium halide and the Lewis acid TiCl4 – a method which afforded the
more stable (Z)-2-(chloromethyl)alkenone diastereomer. Consequently, the
1
Morita–Baylis–Hillman adduct 5a was treated with TiCl4 in dichloromethane, but H

4
K. IDAHOSA ET AL.
Fe, AcOH
EDC,CuCl2,
toluene.
reflux, 3h
OH
O
110 -115 oC,
40 min
CO2Me
CO2Me
O
6a
6e
N
For
For
N
O
NO2
7a
NO2
N
H
R2
OMe
6a,e
8e
R4
R3
CHO
NO2
O
OH
NH
O
OH
R4
R3
R4
R3
THF
For
DABCO,
CHCl3
R2
OMe
R1
For 5a,e
3a-h
5a
9
O
NH
NO2
NO2
R2
NH2
OMe
R2
NEt2
5a-h: R1=OMe
10a
4
Pd-C / H2,
EtOH
Et3N, THF
DMF, POCl3
DCM, r.t.
NEt2
5a,c,d-f,h
For
O
NEt2
N
H
R4
+
OMe
N
H
O
13a,c,d-f,h
R3
NO2
Cl
R2
11a
12a
N
H
H2N
13a,d-f
For
14
R2 R3 R4
THF
a
b
c
d
e
f
H
H
H
H
H
H
H
OH
O
OCH2O
OMe OMe
R4
R3
NH
O
OMe
NH
R4
R3
OMe
OMe H
H
Cl
H
OMe
NO2
R2
H
H
H
H
Cl
H
NO2
g
h
O
R2
15a,d,e
16a e f
, ,
Cu2SO4,
Na ascorbate,
H2O-THF
Cu2SO4,
Na ascorbate,
H2O-THF
NH
N
O
O
HO
N
O
O
For 16f
15a d e
For
, ,
O
NH
N3
O
17
HO
N
N
N
R4
R3
OMe
NH
OH
O
NO2
NH
O
R2
R4
R3
N
OMe
N
N
N
NO2
19f
18a d e
, ,
O
R2
N
O
H
Scheme 1. Synthetic pathways to quinolone derivatives and cinnamate ester–AZT conjugates from
methyl acrylate-derived Morita–Baylis–Hillman adducts (5).
NMR analysis of the material obtained after work-up indicated that the ester had not
undergone any change. A method reported by Yadav et al.,[22] which had been used
successfully in our group in the chlorination and concomitant dehydration of MVK-
derived Morita–Baylis–Hillman adducts,[23] was then explored. This involved addition
of the Morita–Baylis–Hillman adduct to a methanolic HCl solution, generated in situ by

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5
adding acetyl chloride drop-wise to anhydrous methanol (CAUTION! the reaction
between acetyl chloride and methanol is exothermic and cooling in an ice-bath is essen-
1
tial). Unfortunately, H NMR analysis of the material obtained after work-up again
failed to indicate any change. Application of a method reported by Liu et al.,[24] involv-
ing the use of the Vilsmeier–Haack reagent [generated in situ from reaction of phos-
phorus oxychloride (POCl3) and DMF], finally afforded the 2-(chloromethyl)cinnamate
1
esters (13) in 53–96% yield. The apparent absence of any additional H or 13C NMR
signals attributable to diastereomers is indicative of highly stereoselective transforma-
tions, while assignment of the Z-stereochemistry to the isolated 2-(chloromethyl)cinna-
mate esters (13) is based on the absence of NOE interactions between the vinylic and
chloromethylene protons in the NOESY NMR spectrum of the parent system 13a. This
configurational assignment is also consistent with data obtained for the MVK-
derived analogs.[23]
The 2-(chloromethyl)cinnamate esters (13) were treated with 2 equivalents of propar-
gylamine 14 in anhydrous THF at room temperature for 2–3 d to afford the correspond-
ing 2-(propargylamino)cinnamates 15a,d,e. and/or the 4-substituted analogs 16a,e,f
through direct (SN) or, in some cases, allylic (SN’) displacement of chloride. The isomeric
1
products were readily identified by the characteristic H NMR signals in the vinylic
region (d 5.4–6.5 ppm) and corresponding signals in the 13C NMR spectra. Interestingly,
the DEPT 135 spectra for both series of products (15) and (16) reveal positive signals
(between ca. 70 and 80 ppm) for both the terminal and non-terminal alkyne carbons – a
phenomenon observed previously[20] and attributable to the large 2JCH interaction
between the non-terminal alkyne carbon and the terminal alkyne proton.[25]
The final step in the sequence to access the cinnamate ester-AZT conjugates (18) and
(19) involved copper(I)-catalyzed 1,3-dipolar Huisgen cycloaddition[26] of the organic
azide, 30-azido-30-deoxythymidine (AZT) with the propargylamino derivatives (15) and
(16) – a ‘Click chemistry’ method used previously in our research group to access cou-
marin analogs as potential dual-action HIV-1 PR/RT inhibitors.[11] Sodium ascorbate
was used to reduce copper(II) [from the sulfate pentahydrate salt (CuSO4.5H2O)] in situ
to copper(I). Work-up and chromatography afforded the targeted cinnamate ester-AZT
conjugates 18a,d,e in moderate to excellent yields. The SN product 15f could not be iso-
lated in sufficient purity to warrant further reaction, but similar reaction of the 3-(prop-
argylamino)cinnamate ester 16f permitted isolation of the isomeric product 19f in
low yield.
A conformational search was conducted using VEGA ZZ,[27] to obtain the most sta-
ble conformation of the “parent” cinnamate ester-AZT conjugate 18a, which was then
geometry optimized using Gaussian03 at the B3LYP/6-31 G(d) level[28] preparatory to
in silico docking in the HIV-1 IN and RT enzyme active-sites. The X-ray crystallo-
graphic structures of HIV-1 IN (1QS4)[29] and HIV-1 RT (1IKW)[30] were obtained
from the protein databank (PDB), and docking of the ligand 18a into the active sites of
these enzymes was explored using Autodock version 4.[31,32] Figure 2a illustrates the lig-
and 18a superimposed on 5-CITEP, a b–diketo acid (DKA) analog which exhibits HIV-
1 IN inhibition activity,[33] docked within the HIV-1 IN enzyme active-site. While the
AZT moiety clearly extends beyond the IN enzyme active-site, the cinnamate ester moi-
ety appears to be reasonably well accommodated within the active-site. In line with our

6
K. IDAHOSA ET AL.
Figure 2. Graphical representations, visualized using Discovery Studio (DS) Visualizer,[34] of: (a) ligand
18a (coloured) and 5-CITEP (yellow) docked within the HIV-1 integrase (1QS4)[29] active-site; and (b)
ligand 18a in the non-nucleoside active-site of HIV-1 RT (1IKW).[30]
O
O
,
OH
O
R4
R3
R4
R3
R4
R3
CHO
NO2
CH3COBr
Dry EtOH,
Me
Me
Me
NO2
NO2
NH2
Br
DABCO
or 3-HQ,
CHCl3
For 21a,f
R2
R2
R2
,
3a f
20a f
23a,f
CH3COCl
Dry EtOH,
9
Et2N
NEt2
9
O
O
N
R4
R3
R4
H2N
Me
Me
H
X
Cl
R3
NO2
NO2
21a,f
R2
R2
22a,f
10% Pd-C,
H2, EtOH
R2 R3 R4
NEt2
a
f
H
H
H
H
H
Cl
R4
R1
N
24 R1 = NHCH(CH3)(CH2)3NEt2; R4 = H
Scheme 2. Synthetic pathways to quinoline derivatives from MVK-derived Morita–Baylis–Hillman
adducts (20).
dual-action drug strategy, the docking of ligand 18a into the HIV-1 RT non-nucleoside
site (1IKW)[30] was also explored, Figure 2b revealing potential hydrogen-bonding inter-
actions between the ligand and amino acid residues in the binding pocket. It was also
found that the bound ligand 18a aligned well with the superimposed structure of efavir-
enz,[33] a known non-nucleoside reverse transcriptase inhibitor (NNRTI). In vivo tri-
phosphorylation of the AZT hydroxyl group in these ligands might also enable them to
function as inhibitors at the nucleoside (NRTI) site.
Use of the known[23] Morita–Baylis–Hillman MVK adducts (20) and their 2-chloro-
methyl derivatives (21) (Scheme 2) was expected to provide access to 2-butenone

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analogs of the a-(aminomethyl)cinnamate ester 7a and the analogs of the quinolones 8e
and 11a obtained from the Morita–Baylis–Hillman methyl acrylate adducts (5) (Scheme
1). Reactions of the 2-chloromethyl derivatives (21) with 2-amino-5-diethylaminopen-
tane 9, designed to provide access to 3-substituted chloroquine analogs (22), failed to
provide any isolable products, and attention was turned to the use of the bromomethyl
derivatives (23) which were expected to be more susceptible to nucleophilic substitution
than the chloromethyl intermediates (21).
Adapting the method reported by Yadav et al.,[22] the adducts 20a,f were treated with
ethanolic HBr, generated in situ. by adding acetyl bromide cautiously to anhydrous
ꢀ
ethanol at 0 C. Work-up and chromatography afforded the allyl bromides 23a,f which
were then treated with 2 equivalents of 2-amino-5-(diethylamino)pentane in anhydrous
THF to afford the desired amino derivatives 22a (36%) and 22f (58%). Reductive cyc-
lization of compound 22a, using hydrogen and 10% palladium-on-carbon catalyst in
ethanol, gave the expected 3-substituted quinoline 24a in 54% yield. Unfortunately, the
5-chloro analog 22f (which was expected to lead to the 3-substituted isomer of chloro-
quine) afforded the same product 24 in 86% yield, with the critical halogen substituent
having been lost under the reducing conditions.
Conclusions
Morita–Baylis–Hillman methodology has been successfully exploited to provide access
to various, medicinally significant structural motifs. Adducts obtained from DABCO-
catalysed reactions of 2-nitrobenzaldehydes with methyl acrylate have been successfully
elaborated to obtain: a-[(alkylamino)methyl]cinnamate esters; cinnamate ester-azidothy-
midine (AZT) conjugates as potential dual-action HIV-1 integrase-reverse transcriptase
(IN-RT) inhibitors; and 2-quinolone derivatives. Analogous adducts, prepared using
methyl vinyl ketone, have been used to access substituted 3-(aminomethyl)-but-3-en-2-
one and 3-(aminomethyl)quinoline derivatives. Preliminary in silico modeling studies
indicate the capacity of the “parent” cinnamate ester-AZT conjugate 18a to dock into
both the HIV-1 IN and non-nucleoside RT binding sites.
Experimental
The preparation of the Morita–Baylis–Hillman adducts 5a–g and 20a,b,f has been
reported elsewhere.[16] General procedures and data for representative compounds are
detailed below. Analytical data for other new compounds and NMR spectra are pro-
vided in the Supplementary Material.
General procedure for the preparation of the aza-Michael adducts 6a and 6e
A mixture of methyl 3-hydroxy-2-methylene-3-(2-nitrophenyl)propanoate 5a (0.57 g,
2.4 mmol), piperidine (0.5 mL, 5 mmol) and anhydrous THF (5 mL) was stirred in a
stoppered flask for 2d. Excess solvent and unreacted piperidine were evaporated
in vacuo and the residue was flash chromatographed [on silica gel; eluting with hexane-
EtOAc (1:1)] to afford, as a yellow solid, comprising an impure 2:1 diastereomeric

8
K. IDAHOSA ET AL.
mixture, methyl 3-hydroxy-3-(2-nitrophþenyl)-2-[(piperidin-1-yl)methy]propanoate 6a
ꢀ
(0.6 g, 77%) [m.p. 73–75 C (Found MH : 323.1609. Calc. for C16H23N2O5, 323.1607);
ꢀmax (ATR)/cmꢁ1 3396 (OH) and 1716 (C=O) which was used without further
purification.
Methyl 2-[(4-diethylamino-1-methylbutyl)amino-methy]}-3-hydroxy-3-(2-
nitrophenyl)-propanoate 10a
A mixture of methyl 3-hydroxy-2-methylene-3-(2-nitrophenyl)propanoate 5a (1.2 g, 4.9
mmol) and 2-amino-5-diethylaminopentane 9 (0.78 g, 1.0 mL, 4.9 mmol) in anhydrous
THF (2 mL) and triethylamine (0.7 mL) was stirred in a stoppered flask for 2 d. Excess
solvent and unreacted amine were evaporated in vacuo and the residue was purified by
flash chromatography [on silica gel, basified and conditioned overnight with 5% trie-
thylamine in hexane-EtOAc (1:1); eluting sequentially with 5% triethylamine in hexane-
EtOAc (1:1)], followed by 5% methanol in the initial eluent] to afford, as a yellowish-
brown, transparent oil, shown by HRMS (Found MHþ: 396.2494. Calc. for C20H34N3O5,
396.2498) and NMR analysis to comprise a diastereomeric mixture of methyl 2-[(4-
diethylamino-1-methylbutyl)amino-methy]}-3-hydroxy-3-(2-nitrophenyl)propanoate 10a
(1.7 g, 87%), which was used without further purification. Various signals were split
1
due to the presence of the diastereomers, and examination of the integrals for the H
NMR signals at ca. 3.7 and 5.8 ppm suggests a diastereomeric ratio of ca. 3:1.)
3 -[(4-Diethylamino-1-methylbutyl)aminomethyl]-2(1H)-quinolone 11a and 3-
methyl-1,2-dihydroquinoline 12a
To a solution of methyl 3-[(4-diethylamino-1-methylbutyl)aminomethyl]-3-hydroxy-(2-
nitrophenyl)propanoate 10a (0.8 g, 2 mmol) in anhydrous ethanol (10 mL), 10% Pd-C
catalyst (1.3 g) was added and the reaction mixture was stirred under a hydrogen
atmosphere. After 3 h, the reaction mixture was filtered through a bed of Celite to
remove the catalyst. The filtrate was concentrated in vacuo to afford the crude product,
which was then purified by flash chromatography [on a Discovery DSC diol column,
basified and conditioned overnight with 5% triethylamine (TEA) in EtOAc-hexane (1:1);
eluting sequentially with 5% TEA in EtOAc-hexane (1:1), followed by the addition of
5% methanol to the initial eluent] to afford the following fractions.
Fraction I
3-Methyl-1,2-dihydroquinoline 12a (0.14 g, 14%), as a yellowish-brown oil; dH (400
MHz; CDCl3) 2.28 (3 H, s, Ar-CH3), 2.61 (2 H, s, 2-CH2), 7.19 (1 H, t, J = 7.2 Hz, Ar-
H), 7.36 (1 H, d, J = 8.0 Hz, Ar-H), 7.45 (1 H, t, J = 7.6 Hz, Ar-H), 7.50 (1 H, d, J =
8.0 Hz, Ar-H) and 7.64 (1 H, s, C=CH); dC (100 MHz; CDCl3) 29.7 (2-CH2), 40.9
(CH3), 115.5, 120.3, 122.4, 126.9, 129.3, 130.1, 137.4, and 164.4 (Ar-C and C=CH).

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Fraction II
3-[(4-Diethylamino-1-methylbutyl)aminomethyl]-2(1H)-quinolone 11a as a pink oil
which solidified to a wax upon standing (0.22 g, 27%) (Found MHþ: 316.2385. Calc. for
C19H30N3O: 316.2389); ꢀmax (ATR)/cmꢁ1 1653 (C=O); dH (400 MHz; CDCl3) 0.98 (6
H, t, J = 7.2 Hz, 2 ꢂ CH3CH2), 1.13 (3 H, d, J = 7.2 Hz, CH3CH), 1.3–1.5 (4 H, 2 ꢂ
m, CHCH2CH2), 2.41 (2 H, t, J = 7.2 Hz, NCH2), 2.4–2.5 (4 H, m, 2 ꢂ CH2CH3), 2.73
(1 H, m, NCHCH2), 3.79 and 3.88 (2 H, 2 ꢂ d, J = 14.8 Hz, ArCH2), 7.19 (1 H, t, J =
7.2 Hz, Ar-H), 7.39 (1 H, d, J = 8.4 Hz, Ar-H), 7.48 (1 H, t, J = 7.6 Hz, Ar-H) and 7.54
(1 H, d, J = 8.0 Hz, Ar-H); dC (100 MHz; CDCl3) 9.6 (2 ꢂ CH3CH2), 20.2 (CH3CH),
23.0 (NCHCH2), 32.2 (CH2CH2CH2), 46.7 (2 ꢂ NCH2CH3 and ArCH2), 52.2 (NCH2),
53.0 (NCH), 115.6, 120.0, 122.5, 127.4, 129.7, 131.6, 137.2, and 137.6 (Ar-C and C=CH)
and 164.1 (C=O).
General procedure for the synthesis of the 2-(chloromethyl) derivatives (13)
Phosphorus oxychloride (POCl3) (2 eq.) was added to DMF and the resulting mixture
was stirred at room temperature for 10 min. CH2Cl2 was then added, followed by a
solution of the Morita–Baylis–Hillman adduct (5) (1 Eq.) in CH2Cl2, in one portion.
The mixture was stirred at room temperature and the reaction monitored (TLC) until
completion. Water was added, and the organic phase was separated and washed with
brine, dried over anhydrous MgSO4 and concentrated in vacuo to give the crude prod-
uct. Purification by flash chromatography [on silica gel; eluting with hexane: EtOAc
(5:1)] afforded the desired product (13). The different solid products varied in color
from light to intensely deep yellow. Compound 13a is known,[24] and data for the other,
new analogs are provided in the Supporting Information file.
General procedure for the reaction of the 2-chloromethyl derivatives (13) with
propargylamine 14
A solution of the allyl chloride (13) (1 Eq.) and propargylamine 14 (2 Eq.) in anhydrous
THF was stirred in a stoppered flask at room temperature for periods which varied
according to the reactants involved. The solution was then concentrated in vacuo and
the crude product purified by flash chromatography to afford the aminated product(s).
Reaction of (Z)-2-(chloromethyl)-3-(2-nitrophenyl)propenoate 13a with
propargyl-amine
Work-up and flash chromatography [on silica gel; eluting with EtOAc-hexane (1:1)]
afforded two fractions.
Fraction I
Methyl (E)-3-(2-nitrophenyl)-2-[(prop-2-ynylamino)methyl]propenoate 15a as light
þ
ꢀ
ꢃ
lemon-yellow crystals (0.25 g, 56%), m.p. 53–55 C (Found MH : 275.1025. Calc. for
C14H15N2O4, 275.1032); ꢀmax (ATR)/cmꢁ1 1718 (C=O); dH (400 MHz; CDCl3) 1.82 (1

10
K. IDAHOSA ET AL.
H, br s, NH), 2.03 (1 H, s, CꢄCH), 3.33 (2 H, d, J = 2.0 Hz, CH2NH), 3.48 (2 H, s,
CH2CꢄCH), 3.84 (3 H, s, CH3), 7.52 (1 H, t, J = 7.4 Hz, 40-H), 7.60 (1 H, d, J = 7.6
Hz, 60-H), 7.65 (1 H, t, J = 7.6 Hz, 50-H), 8.04 (1 H, s, 3-H) and 8.14 (1 H, d, J = 8.4
Hz, 30-H); dC (100 MHz; CDCl3) 37.6 and 44.9 (2 x NCH2), 52.3 (CO2CH3), 71.3 and
81.5 (CꢄCH), 124.8, 129.4, 131.1, 131.3, 131.7, 133.5, 138.9 and 147.6 (Ar-C and C =
1
ꢃ
CH) and 167.5 (C=O). ca. 90% pure as estimated from H NMR integrals.
Fraction II
Methyl 3-(2-nitrophenyl)-2-methylene-3-(prop-2-ynylamino)propanoate 16a as an
1
impure off-white solid (ca. 10% of initial mixture) identified by inspection of the H-
and 13C-NMR spectra.
General procedure for the synthesis of the cinnamate ester-AZT conjugates (18)
and (19)
To a solution of 3’-azido-3’-deoxythymidine (AZT) 17 (1 Eq.) in H2O-THF (1:1) was
added the propargylamine derivative(s) (7 or 8 or mixtures thereof) (1 Eq.), sodium
ascorbate (0.2 Eq.) and copper sulfate pentahydrate (CuSO4.5H2O; 0.03 Eq.). After stir-
ring at room temperature for 24 h, the mixture was extracted with CH2Cl2, and the
organic phase was washed sequentially with H2O and brine, and then dried over anhyd-
rous MgSO4. The solution was concentrated in vacuo to give the crude product, which
was purified by flash chromatography [on silica gel; eluting with EtOAc, followed by
MeOH-EtOAc (2:3)] to afford the Morita–Baylis–Hillman-derived ester-AZT conjugates
(18) and/or (19).
The cinnamate ester-AZT conjugate 18a1 as lemon-yellow flakes (0.14 g, 44%), m.p.
106–108 ꢀC (Found MHþ: 542.1998. Calc. for C24H28N7O8, 542.1999); ꢀmax (ATR)/
cmꢁ1 3321 (OH) and 1682 (C=O); dH (400 MHz; methanol-d4) 1.90 (3 H, s, ArCH3),
2.6–2.8 (2 H, 2 ꢂ m, NCHCH2), 3.31 (2 H, m, NCH2), 3.76 (2 H, s, NCH2), 3.70–3.83
(4 H, m overlapped by s, CHaOH and OCH3), 3.8–3.9 (1 H, m, CHbOH overlapped by
solvent signal), 3.87 (3 H, s, 4.30 (1 H, m, NCH), 5.33 (1 H, m, CHCH2OH), 6.44 (1 H,
m, NCHO), 7.4-8.2 (7 H, series of signals, Ar-H and CH = C); dC (100 MHz; metha-
nol-d4) 12.6 (ArCH3), 39.2 (CHCH2), 44.2 and 45.7 (2 ꢂ CH2NH), 53.0 (CO2CH3), 61.2
(CH2OH), 62.3 (NCH), 86.5 (CHCH2OH), 86.8 (NCHO), 111.8, 124.0, 126.1, 131.2,
132.1, 132.3, 132.7, 135.1, 138.4, 140.8, 147.2 and 149.1 (Ar-C and CH=C), 152.4, 166.5
and 169.0 (3 ꢂ C=O).
General procedure for the synthesis of the (Z)-3-(chloromethyl)-4-(2-
nitrophenyl)but-3-en-2-one derivatives (21)
A solution of 4-hydroxy-3-methylene-4-(2-nitrophenyl)butan-2-one 20a (0.11 g, 0.50
mmol) in ethanol (0.5 mL) was added to ethanolic HCl [generated iꢀn situ by adding
acetyl chloride (0.5 mL) dropwise to anhydrous ethanol (1.0 mL) at 0 C (CAUTION –
exothermic reaction!) in a two-necked flask fitted with a reflux condenser and a drop-
ping funnel and leaving the mixture to stir for 5 min.]. Stirring was continued at room

R
SYNTHETIC COMMUNICATIONSV
11
temperature overnight. Excess solvent and unreacted HCl were evaporated in vacuo to
afford, as a light-brown powder, (Z)-3-(chloromethyl)-4-(2-nitrophenyl)but-3-en-2-one
[35]
ꢀ
ꢀ
120–122 C).
21a (0.12 g, 99%), m.p. 121–122 C, (lit.
General procedure for the synthesis of the (E)-3-[(4-diethylamino-1-
methylbutyl)aminomethyl]-4-(2-nitrophenyl)]but-3-en-2-ones (22)
To a solution of 3-bromomethyl-4-(2-nitrophenyl)]but-3-en-2-one 23a (0.4 g, 2.0 mmol)
in anhydrous THF (2.0 mL) was added 2-amino-5-(diethylamino)pentane (0.57 mL, 3.0
mmol), and the mixture was left to stir in a stoppered flask at room temperature for 7 d.
Work-up and flash chromatography [on basified silica gel; eluting with 5% triethylamine
in hexane-EtOAc (1:1)] afforded (E)-3-[(4-diethylamino-1-methylpentylaminomethyl]-
4-(2-nitrophenyl)]but-3-en-2-one 22a as brown wax (0.2 g, 36%) (Found MHþ: 362.2446.
Calc. for C20H32N3O3, 362.2444); ꢀmax (ATR)/cmꢁ1 1716 (C=O); dH (400 MHz; CDCl3)
0.9–1.1 (9 H, m, 3 ꢂ CH3), 1.1–1.5 (4 H, 2 ꢂ m, CHCH2CH2), 2.38 (3 H, s, CH3CO),
2.4–2.6 (7 H, overlapping m, CH3CH and 3 ꢂ NCH2), 3.19 and 3.30 (2 H, 2 ꢂ d, J = 12
Hz, CHCH2NH), 4.99 (1 H, br s, NH), 7.49 (1 H, m, Ar-H), 7.63 (1 H, m, Ar-H), 7.70 (1
H, d, J = 8 Hz, Ar-H), 7.83 (1 H, s, 4-H) and 8.10 (1 H, d, J = 8 Hz, Ar-H); dC (100 MHz;
CDCl3); 10.2 (2 ꢂ CH3CH2), 19.4 (CH3CH), 21.7 (CHCH2CH2), 25.6 (CH3CO), 34.1
(CHCH2CH2) 42.4 (NCH2), 45.8 (2 ꢂ NCH2CH3), 51.7 (CH2NH) 52.3 (CH3CH), 124.4,
129.2, 130.6, 131.3, 133.1, 138.2, 139.8, and 146.7 (Ar-C and C=CH) and 199.8 (C=O).
General procedure for the synthesis of the (Z)-3-(bromomethyl)-4-(2-
nitrophenyl)but-3-en-2-one derivatives (23)
A solution of 4-hydroxy-3-methylene-4-(2-nitrophenyl)butan-2-one 20a (1.1 g, 4.4
mmol) in ethanol (2.0 mL) was added to ethanolic HBr [generated in situ by adding ace-
ꢀ
tyl bromide (1.5 mL, 8.8 mmol) dropwise to dry ethanol (5.0 mL) at 0 C (CAUTION –
exothermic reaction!) in a two-necked flask fitted with a reflux condenser and a dropping
funnel, and the mixture was left to stir for 5 min]. Stirring was continued at room tem-
perature overnight. Excess solvent and unreacted HBr were evaporated in vacuo and flash
chromatography of the residue [on silica gel; eluting with EtOAc-hexane (1:3)] afforded
(Z)-3-(bromomethyl)-4-(2-nitrophenyl)but-3-en-2-one 23a as a light-brown powder
ꢀ
(0.80 g, ca. 64%), m.p. 118–120 C, which was used without further purification; ꢀmax
(ATR)/cmꢁ1 1671 (C=O); dH (400 MHz; CDCl3) 2.53 (3 H, s, CH3), 4.07 (2 H, s, CH2Br),
7.63 (1 H, t, J = 7.6 Hz, Ar-H), 7.80 (2 H, m, Ar-H), 7.95 (1 H, s, 4-H) and 8.25 (1 H, d, J
= 8.0, Ar-H); dC (100 MHz; CDCl3) 23.9 (CH2Br), 26.1 (C-1), 125.3, 129.9, 130.1, 130.4,
134.1, 138.1, 139.5, and 147.0 (Ar-C and C=CH) and 196.6 (C=O).
3 -[(4-Diethylamino-1-methylbutyl)aminomethyl]-2-methylquinoline 24
Method 1
To a solution of 3-[(4-diethylamino-1-methylbutyl)aminomethyl]-4-(2-nitrophenyl)but-
3-en-2-one 22a (0.2 g, 0.5 mmol) in anhydrous ethanol (8 mL), 10% Pd–C catalyst (0.9
g) was added, and the mixture was stirred under a hydrogen atmosphere for 3 h. The

12
K. IDAHOSA ET AL.
reaction mixture was filtered through a bed of Celite to remove the catalyst. The filtrate
was concentrated in vacuo and the residue was flash chromatographed [on a Discovery
DSC diol column, basified and conditioned overnight with 5% triethylamine (TEA) in
EtOAc-hexane (1:1); eluting sequentially with 5% TEA in EtOAc-hexane (1:1), followed
by the addition of 5% methanol to the initial eluent] to afford 3-[(4-diethylamino-1-
methylbutyl)aminomethyl]-2-methylquinoline 24 as a brown oil (0.1 g, 54%) (Found
MHþ: 314.2593. Calc. for C20H32N3: 314.2596); dH (400 MHz; CDCl3) 0.7–1.6 (13 H,
overlapping multiplets, 3 ꢂ CH3 and CHCH2CH2), 2.42 (2 H, t, J = 7.2 Hz, NCH2),
2.4–2.5 (5 H, m, NCH, 2 ꢂ NCH2CH3), 2.74 (3 H, s, 2-CH3), 3.84 and 3.94 (2 H, 2 ꢂ
d, J = 13.6 Hz, NCH2CH2), 7.58 (1 H, t, J = 7.6 Hz, Ar-H), 7.68–7.71 (2 H, m, 2 ꢂ Ar-
H), 7.79 (1 H, d, J = 8.0 Hz, Ar-H) and 8.72 (1 H, d, J = 8.8 Hz, Ar-H); dC (100 MHz;
CDCl3) 11.4 (2 ꢂ CH3CH2), 14.4 (CH3CH), 20.5 (2-CH3), 23.5 (CHCH2CH2), 35.1
(CHCH2CH2), 46.7 (ArCH2N), 49.0 (2 ꢂ CH3CH2N), 53.0 (NCH2), 53.2 (CHN), 119.6,
124.7, 127.7, 127.8, 128.8, 129.8, 133.7, 140.2, and 146.3 (Ar-C).
Method 2
4-(5-Chloro-2-nitrophenyl)-3-[(4-diethylamino-1-methylbutyl)aminomethyl]but-3-en-2-
one 22f was reacted with 10% Pd-C catalyst (1.0 g), following the procedure in Method
1
1. Work-up afforded a brown oil, indicated by H and 13C NMR and HRMS analysis to
be 3-[(4-diethylamino-1-methylbutyl)aminomethyl]-2-methylquinoline 24.
Note
1. Systematic
name:
4{[2-methoxycarbonyl-3-(2-nitrophenyl)-2-propenylamino]methyl}-1-
[(2S,3R,5R)-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-2-
(hydroxymethyl)tetrahydrofuran-3-yl]-1H-1,2,3-triazole.
Acknowledgements
The authors thank Rhodes University for bursary support (K.C.I.) and the National Research
Foundation (NRF: GUN 2069255), the Medical Research Council of South Africa (SAMRC) and
Rhodes University for generous financial support. Any opinion, findings and conclusions or rec-
ommendations expressed in this material are those of the authors and therefore the NRF does
not accept any liability in regard thereto. Prof K.A. Lobb’s guidance in computer modelling and
ligand docking is appreciated.
Funding
The authors thank Rhodes University for bursary support (K.C.I.), the National Research
Foundation (NRF: GUN 2069255), and the South African Medical Research Council (SAMRC)
for generous financial support.
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