Indolizine studies, part 5: Indolizine-2-carboxamides as potential HIV-1 protease inhibitors[1]

Article abstract of DOI:10.1080/00397910903219450

1,1-Carbonyldiimidazole-promoted coupling of Baylis-Hillman-derived indolizine-2-carboxylic acids with a range of amine and amino acid derivatives has provided access to the corresponding carboxamides in moderate to excellent yield. Copyright

Full text of DOI:10.1080/00397910903219450

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Indolizine Studies, Part 5: Indolizine-2-
carboxamides as Potential HIV-1
Protease Inhibitors[ ]
Matshawandile Tukulula a , Rosalyn Klein a & Perry T. Kaye a
a Department of Chemistry and Centre for Chemico- and
Biomedicinal Research , Rhodes University , Grahamstown, South
Africa
Published online: 08 Jun 2010.
To cite this article: Matshawandile Tukulula , Rosalyn Klein & Perry T. Kaye (2010) Indolizine Studies,
Part 5: Indolizine-2-carboxamides as Potential HIV-1 Protease Inhibitors[ ] , Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:13, 2018-2028,
DOI: 10.1080/00397910903219450
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Synthetic Communications1, 40: 2018–2028, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219450
INDOLIZINE STUDIES, PART 5: INDOLIZINE-
2-CARBOXAMIDES AS POTENTIAL HIV-1
PROTEASE INHIBITORS[1]
Matshawandile Tukulula, Rosalyn Klein, and Perry T. Kaye
Department of Chemistry and Centre for Chemico- and Biomedicinal
Research, Rhodes University, Grahamstown, South Africa
1,1-Carbonyldiimidazole-promoted coupling of Baylis–Hillman-derived indolizine-2-
carboxylic acids with a range of amine and amino acid derivatives has provided access to
the corresponding carboxamides in moderate to excellent yield.
Keywords: Baylis–Hillman reaction; HIV-1 protease inhibitors; indolizine-2-carboxamides
The HIV=AIDS pandemic has already been responsible for the death of
millions of people worldwide, and it is estimated that there are 5 million new infec-
tions every year.[2] The development of inhibitors that target key enzymes in the
HIV-1 life cycle, namely, reverse transcriptase (HIV-RT),[3] integrase (HIV-IN),[4]
and protease (HIV-PR),[5] has improved life expectancy. However, the efficacy of
these drugs has been mitigated by the development of resistance and the unpleasant
side effects, which, in turn, may lead to patient non-compliance. Although the prob-
lem of drug resistance has been addressed, at least temporarily, by the implemen-
tation of highly active antiretroviral therapy (HAART), which involves the
combination of HIV-PR and HIV-RT inhibitors,[6] there is an urgent need for
new, improved, and cost-effective anti-HIV drugs.
In an earlier study, we reported the preparation of analogs of the HIV-1 pro-
tease inhibitor ritonavir.[7] In this approach, Baylis–Hillman-derived chromene, cou-
marin, and thiochromene heterocyclic systems were attached to the amino termini
of the hydroxyethylene dipeptide isostere, present in ritonavir 1. We have, subse-
quently, been exploring the construction of novel, and more synthetically accessible,
truncated analogs in which various heterocyclic moieties are linked to a
peptido-mimetic chain as illustrated in Fig. 1.
Indolizine derivatives have been reported to exhibit valuable biological activity
as potential calcium entry blockers,[8] cardiovascular agents,[8,9] anti-5-hydroxytryp-
tamine,[10] antihistamine,[10] antitumor,[11] anti-Mycobacterium tuberculosis (TB),[12]
anticancer,[8,13] and anti-HIV[8,14] agents. Various approaches have been developed
Received April 22, 2009.
Address correspondence to Perry T. Kaye, Department of Chemistry and Centre for Chemico- and
Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa. E-mail: P.Kaye@ru.ac.za
2018

INDOLIZINE-2-CARBOXAMIDES
2019
Figure 1. Design rationale for truncated analogs.
for the synthesis of indolizine derivatives.[15] These include condensation reactions
(i.e., the Scholtz[15] and Chichibabin reactions[16]), 1,3-dipolar cycloaddition,[17]
and an approach pioneered in our own group involving the use of Baylis–Hillman
methodology.[18] Attention has also been given to the preparation and rotational
isomerism of a series of indolizine-2-carboxamides.[19] In an extension of these earlier
studies, we now report the synthesis and characterization of a series of
indolizine-based truncated analogs of the hydroxyethylene dipeptide isosteres, typi-
fied by ritonavir.
The indolizine-2-carboxylate esters 6a–c were prepared using the methodology
developed previously[18] (Scheme 1). Thus, the pyridine-2-carbaldehydes 2a–c were
treated with methyl acrylate 3 and 1,4-diazabicyclo[2.2.2]octane (DABCO) (or
3-hydroxyquinuclidine) in chloroform to afford the Baylis–Hillman adducts 4a–c.
Cyclization to the corresponding indolizine-2-carboxylate esters 6a–c was effected
by heating the acetates 5a–c in acetic anhydride at 120 ꢀC for 30 min. Acetylation
Scheme 1. Synthesis of indolizine scaffolds. Reagents and conditions: (i) DABCO or 3-hydroxyquinucli-
dine, CHCl3; (ii) Ac2O, 100 ꢀC, 30 min; (iii) 120 ꢀC, 1 h; and (iv) KOH, EtOH, reflux, 16 h, then dil. HCl.

2020
M. TUKULULA, R. KLEIN, AND P. T. KAYE
Scheme 2. Proposed mechanism for the formation of methyl 1-acetoxypyrrolo[1,2-a]quinoline-2-
carboxylate 7c.
of the alcohol precursors 4a–c (at 100 ꢀC for 30 min) has been found to facilitate
cyclization,[18] but, not surprisingly under these conditions, the acetylated products
may be accompanied by some of the corresponding cyclized derivatives. In the case
of the quinoline derivative 4c, the acetylated product 5c was accompanied not only
by the corresponding indolizine 6c but also by the unexpected 1-acetoxyindolizine 7c
as a minor product (ca. 6%). Both the presence of the acetoxy moiety (a good leaving
group) and its location at C-1 rather than C-3 were surprising, and the formation of
this minor product is attributed to allylic displacement of the 3-acetoxy group,
followed by an aza-Nazarov cyclization as illustrated in Scheme 2. A kinetic–
mechanistic study of the cyclization step (5 ! 6) has already been published.[1] The
indolizine-2-carboxylate esters were saponified using ethanolic potassium hydroxide;
neutralization then afforded the carboxylic acids 8a–c, required as precursors for the
title carboxamides, in moderate yield (57–65%).
With the indolizine-2-carboxylic acids 8a–c in hand, attention could be
turned to the formation of the series of amide derivatives. Earlier studies had indi-
cated that the best general method for accessing indolizine-2-carboxamides
involved direct reaction of the carboxylic acid with the amine in the presence of
the coupling agent, carbonyl diimidazole (CDI) in dry dimethylformamide
(DMF).[19] In the present study, the amino compounds chosen for reaction were
1-methyl-5-(diethylamino)butylamine 12, S-benzylcysteamine 13, glycine ethyl
ester 14, L-serine ethyl ester 15, glycine methyl ester 16, L-proline methyl ester
17, and the dipeptide, N-acetyl-glycine-lysine methyl ester 18. Compounds 12–17
were used as the hydrochloride salts and compound 18 was used as the acetate salt;
in these cases, pyridine was added as a base to release the free amino compound.
The indolizine-2-carboxylic acids 8a–c and CDI were each dissolved in dry DMF
(with pyridine for reactions involving salts), and the resulting mixtures were
heated at 40 ꢀC for 5 min. After cooling to room temperature, the amino com-
pound (12–18 or their hydrochloride salts) was added, and the mixture was stirred
overnight at room temperature (Scheme 3). Purification of the crude products was
achieved using preparative layer chromatography to afford the corresponding
indolizine-2-carboxamide derivatives 19–25 in 64–97% yield (Table 1). The pro-
ducts were all characterized by spectroscopic [infrared (IR), one- and two-
dimensional NMR] and elemental [high-resolution mass spectrometry (HRMS)]
analysis.
Baylis–Hillman methodology has thus been successfully used to access a range
of 13 novel N-substituted indolizine-2-carboxamides as truncated ritonavir analogs.
Enzyme-binding, enzyme-inhibition, and in silico enzyme receptor-site docking stu-
dies of these compounds are planned to explore their potential as readily accessible
HIV-1 protease inhibitors.

INDOLIZINE-2-CARBOXAMIDES
2021
Scheme 3. Formation of carboxamide derivatives 19–25. Reagents and conditions: CDI, DMF, 40 ꢀC then
amino compounds 12–18 (as ꢁhydrochloride or ꢁꢁacetate salt with pyridine), rt, overnight.
Table 1. Isolated yields of the indolizine-2-carboxamides 19–25 (Scheme 3)
Compound
R1
R2
R3
Yield (%)
19
H
H
H
H
H
-CH(CH3)(CH2)3N(CH2CH3)2
-(CH2)2SCH2Ph
-(CH2)2SCH2Ph
69
64
79
97
66
40
47
44
34
82
70
50
60
20a
20b
20c
21a
21b
22a
22b
22c
23b
23c
24
Me
-(CH)4-
-(CH2)2SCH2Ph
-CH2CO2Et
-CH2CO2Et
H
H
H
H
H
Me
H
-CH(CH2OH)CO2Et
-CH(CH2OH)CO2Et
-CH(CH2OH)CO2Et
-CH2CO2Me
Me
-(CH)4-
-(CH)4-
H
Me
-CH2CO2Me
-CH2(CH2)2CH(CO2Me)-
-CH2(CH2)3CH(CO2Me)NHCH2NHAc-
H
H
Me
H
25

2022
M. TUKULULA, R. KLEIN, AND P. T. KAYE
EXPERIMENTAL
Low-resolution mass spectra were obtained on a Finnegan Mat GCQ
spectrometer, whereas HRMS were recorded on Micromass 70-70E (University of
the North-West) and Waters API-Q-TOF Ultima spectrometers (University of
Stellenbosch). NMR spectra were recorded on a Bruker 400 MHz AVANCE spec-
trometer and were referenced using solvent signals (dH: 7.26 ppm for residual CHCl3
and dC: 77.0 ppm for CDCl3). IR spectra were recorded on a Perkin-Elmer Fourier
transform (FT)–IR Spectrum 2000 spectrometer using nujol mulls or thin films.
Melting points were determined using a Reichert hot-stage apparatus and are uncor-
rected. Reagents used in this project were supplied by Aldrich and used without
further purification. The indolizine-2-carboxylate esters 6a–c and the corresponding
acids 8a–c are known and were obtained following reported procedures.[18,19] The
novel carboxamides 19–25 were prepared as follows.
N-[4-(Diethylamino)-1-methylbutyl]indolizine-2-carboxamide 19
Indolizine-2-carboxylic acid 8a (0.100 g, 0.63 mmol) was dissolved in dry DMF
(3 ml) in a round-bottomed flask fitted with a reflux condenser and a drying tube.
1,10-Carbonyldiimidazole (CDI) (0.160 g, 0.954 mmol) was added to the mixture,
which was heated at 40 ꢀC for 5 min. The mixture was allowed to cool to room tem-
perature, 1-methyl-5-(diethylamino)butylamine 12 (0.245 g, 1.55 mmol) was added,
and the resulting mixture was stirred overnight. The reaction was then quenched
with water (1 ml), and the solvent was removed under reduced pressure. Aqueous
Na2CO3 (1 M, 15 ml) was added to the residue, and the mixture was extracted with
EtOAc (2 ꢂ 24 ml) and then washed sequentially with water (24 ml) and saturated
brine (24 ml). The extract was dried over MgSO4, and the solvent removed in vacuo
to afford a yellow oil (0.241 g), which was purified by flash chromatography [on
silica; elution with CH2Cl2–aqueous ammonia–methanol (20:4:1)] to afford N-
[4-(diethylamino)-1-methylbutyl]indolizine-2-carboxamide 19 as a yellow oil (0.132g,
69.4%). Found Mþ: 301.216652; C18H27N3O requires M, 301.215413. nmax(KBr)=
cmꢃ1 1609 (NHC¼O); dH (400 MHz; CDCl3) 1.00 (6H, t, J 7.2 Hz, 2 ꢂ CH3CH2),
1.25 (3H, d, J 6.8 Hz, CHCH3), 1.55 (4H, m, CH2CH2CH2N), 2.44 (2H, t, J 3.2 Hz,
CH2CH2N), 2.52 (4H, q, J 7.2 Hz, CH3CH2N), 4.21 (1H, m, CHCH3), 6.02 (1H, d,
J 9.6 Hz, NH), 6.51 (1H, m, Ar-H), 6.56 (1H, s, Ar-H), 6.68 (1H, m, Ar-H), 7.34
(1H, d, J 9.2 Hz, Ar-H), 7.74 (1H, d, J 0.8 Hz, Ar-H) and 7.86 (1H, dd, J 7.0 and
0.6 Hz, Ar-H); dC (100MHz; CDCl3) 11.5 (q), 21.1 (q), 23.6 (t), 35.0 (t), 45.1 (d),
46.8 (t), 52.7 (t), 96.9 (d), 111.8 (d), 113.9 (d), 118.2 (d), 119.8 (d), 124.2 (s), 125.4
(d), 132.8 (s) and 164.1 (s).
N-[2-(Benzylthio)ethyl]indolizine-2-carboxamide 20a
Indolizine-2-carboxylic acid 8a (0.100 g, 0.63 mmol) in dry DMF (5 ml) and dry
pyridine (3 ml) was reacted with S-benzylcysteamine hydrochloride 13 (0.200 g,
0.960 mmol), following the procedure described for the preparation of N-
[4-(diethylamino)-1-methylbutyl]indolizine-2-carboxamide 19, to afford a crude
product, which was purified by preparative layer chromatography [on silica; elution

INDOLIZINE-2-CARBOXAMIDES
2023
with CH2Cl2–methanol (20:4)] to afford N-[2-(benzylthio)ethyl]indolizine-2-carbox-
amide 20a as a yellow solid (0.12 g, 65%), mp 104–106 ꢀC. Found Mþ: 310.113786;
C18H18N2OS requires M, 310.113985. nmax(KBr)=cmꢃ1 1652 (C¼O); dH (400 MHz;
CDCl3) 2.69 (2H, t, J 6.4 Hz, CH2CH2S), 3.61 (2H, m, CH2CH2S), 3.76 (2H, s,
CH2Ar), 6.38 (1H, br s, NH), 6.52 (1H, m, Ar-H), 6.57 (1H, s, Ar-H), 6.70 (1H,
dd, J 8.4 and 6.8 Hz, 6-H), 7.24 (1H, m, Ar-H), 7.33 (5H, m, Ar-H), 7.74 (1H, d,
J 1.2 Hz, Ar-H) and 7.88 (1H, d, J 6.4 Hz, Ar-H); dC (100 MHz; CDCl3) 31.3 (t),
35.8 (t), 37.9 (t), 97.1 (d), 111.9 (d), 114.0 (s), 118.3 (d), 120.0 (d), 123.5 (s), 125.4
(d), 127.1 (d), 128.6 (d), 128.8 (d), 132.9 (s), 138.1 (s) and 164.7 (s).
N-[2-(Benzylthio)ethyl]-5-methylindolizine-2-carboxamide 20b
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, S-benzylcysteamine hydrochloride 13 (0.200 g,
0.960 mmol) was reacted with 5-methylindolizine-2-carboxylic acid 8b (0.100 g,
0.571 mmol) to afford N-[2-(benzylthio)ethyl]-5-methylindolizine-2-carboxamide
20b as a green oil (0.147 g, 78.9%). Found M þ 1: 325.1376; C19HN21OS requires
MHþ, 325.1376. nmax(KBr)=cmꢃ1 1642 (C¼O); dH (400 MHz; CDCl3) 2.46 (3H, s,
5-CH3), 2.69 (2H, t, J 6.8 Hz, 11-CH2), 3.61 (2H, q, J 6.8 and 7.2 Hz, 10-CH2),
3.74 (2H, s, ArCH2), 6.40 (1H, d, J 6.8 Hz, Ar-H), 6.68 (3H, m, Ar-H and NH),
7.23–7.34 (6H, overlapping signals, Ar-H) and 7.70 (1H, s, Ar-H); dC (100 MHz;
CDCl3) 18.5 (q), 31.1 (t), 35.7 (t), 38.0 (t), 97.5 (d), 110.9 (d), 111.3 (d), 117.4 (d),
118.6 (d), 123.3 (s), 127.0 (d), 128.5 (d), 128.7 (d), 133.1 (s), 133.5 (s), 138.0 (s)
and 165.0 (s).
N-[2-(Benzylthio)ethyl]pyrrolo[1,2-a]quinoline-2-carboxamide 20c
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, S-benzylcysteamine hydrochloride 13 (0.200 g,
0.960 mmol) was reacted with pyrrolo[1,2-a]quinoline-2-carboxylic acid 8c (0.100 g,
0.47 mmol) to afford N-[2-(benzylthio)ethyl]pyrrolo[1,2-a]quinoline-2-carboxamide
20c as a yellow oil (0.162 g, 96.7%). Found M þ 1: 361.1389; C22H21N2OS requires
MHþ, 361.1375. nmax(KBr)=cmꢃ1 1732 (C¼O); dH (400 MHz; CDCl3) 2.71 (2H, t,
J 6.4 Hz, NCH2CH2), 3.63 (2H, m, NCH2), 3.76 (2H, s, ArCH2), 6.68 (2H, m,
Ar-H and NH), 6.99 (1H, d, J 9.2 Hz, Ar-H), 7.20–7.34 (7H, overlapping signals,
Ar-H), 7.46 (1H, m, Ar-H), 7.59 (1H, d, J 7.6 Hz, Ar-H), 7.81 (1H, d, J 8.0 Hz,
Ar-H) and 8.34 (1H, s, Ar-H); dC (100 MHz; CDCl3) 31.2 (t), 35.8 (t), 38.1 (t),
100.5 (d), 114.0 (d), 114.3 (d), 118.7 (d), 120.3 (d), 122.6 (s), 123.9 (s), 124.5 (d),
127.0 (d), 128.1 (d), 128.5 (d), 128.6 (d), 128.8 (d), 131.2 (s), 132.8 (s), 138.0 (s)
and 164.6 (s).
N-Carbethoxymethylindolizine-2-carboxamide 21a
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, glycine ethyl ester hydrochloride 14 (0.200 g,
1.40 mmol) was reacted with indolizine-2-carboxylic acid 8a to afford N-
[(carbethoxy)methyl]indolizine-2-carboxamide 21a as a green oil (0.097 g, 66%).

2024
M. TUKULULA, R. KLEIN, AND P. T. KAYE
Found Mþ: 246.099889; C13H14N2O3 requires M, 246.100442. nmax(KBr)=cmꢃ1 1637
(NHC¼O) and 1705 (C¼O); dH (400 MHz; CDCl3) 1.31 (3H, t, J 7.2 Hz, CH3), 4.24
(2H, s, NCH2), 4.27 (2H, q, J 7.2 Hz, CH3CH2), 6.50–6.54 (2H, overlapping signals,
Ar-H), 6.64 (1H, s, NH), 6.69 (1H, m, Ar-H), 7.36 (1H, d, J 9.2 Hz, Ar-H), 7.77 (1H,
s, Ar-H) and 7.88 (1H, d, J 6.8 Hz, Ar-H); dC (100 MHz; CDCl3) 14.2 (q), 41.5 (t),
61.6 (t), 97.3 (d), 112.0 (d), 114.1 (d), 118.3 (d), 120.0 (d), 122.9 (s), 125.4 (d),
132.9 (s), 164.7 (s) and 170.3 (s).
N-Carbethoxymethyl-5-methylindolizine-2-carboxamide 21b
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, 5-methylindolizine-2-carboxylic acid 8b
(0.100 g, 0.571 mmol), and glycine ethyl ester hydrochloride 14 (0.200 g, 1.40 mmol)
were reacted to afford N-carbethoxymethyl-5-methylindolizine-2-carboxamide 21b
as a yellow oil (0.059 g, 39.9%). Found M þ 1: 261.1250; C14H17N2O3 requires
MHþ, 261.1239. nmax(KBr)=cmꢃ1 1647 (NHC¼O) and 1693 (C¼O); dH (400 MHz;
CDCl3) 1.29 (3H, t, J 7.2 Hz, CH3CH2), 2.45 (3H, s, Ar-CH3), 4.24 [4H, overlapping
s and q (J 7.2 Hz), NCH2 and CH3CH2], 6.38 (1H, d, J 6.8 Hz, Ar-H), 6.66–6.70 (2H,
overlapping signals, Ar-H), 6.80 (1H, br s, NH), 7.26 (1H, t, J 4.6 Hz, Ar-H) and
7.68 (1H, s, Ar-H); dC (100 MHz; CDCl3) 14.1 (q), 18.5 (q), 41.5 (d), 61.5 (d), 97.9
(d), 111.0 (d), 111.3 (d), 117.5 (d), 118.6 (d), 122.6 (s), 133.1 (s), 133.5 (s), 165.1
(s) and 170.4 (s).
Ethyl (2S)-3-Hydroxy-2-(indolizine-2-carboxamido)propanoate 22a
Following the procedure described for the synthesis of N-[2-(benzylthio)ethyl]-
indolizine-2-carboxamide 20a, L-serine ethyl ester hydrochloride 15 (0.200 g,
1.18 mmol) was reacted with indolizine-2-carboxylic acid 8a to afford ethyl (2S)-3-
hydroxy-2-(indolizine-2-carboxamido)propanoate 22a as a yellow oil (0.080 g,
47%). Found Mþ: 276.109981; C14H16N2O4 requires M, 276.111007. nmax(KBr)=
cmꢃ1 1633 (NHC¼O) and 1700 (C¼O); dH (400 MHz; CDCl3) 1.27 (4H, t, J
6.8 Hz, CH3CH2 and overlapping OH signal), 4.04 (2H, d, J 3.6 Hz, CHCH2),
4.24 (2H, q, J 6.0 Hz, CH3CH2), 4.83 (1H, m, CHCH3), 6.45 (1H, m, Ar-H), 6.63
(2H, m, Ar-H), 7.18 (1H, d, J 7.2 Hz, NH), 7.24 (1H, s, Ar-H), 7.71 (1H, d, J
1.2 Hz, Ar-H) and 7.76 (1H, dd, J 7.0 and 1.0 Hz, Ar-H); dC (100 MHz; CDCl3)
14.4 (q), 55.4 (d), 62.2 (t), 63.8 (t), 98.0 (d), 112.2 (d), 114.5 (d), 118.6 (d), 120.2
(d), 122.8 (s), 125.7 (d), 133.1 (s), 165.6 (s) and 171.1 (s).
Ethyl (2S)-3-Hydroxy-2-(5-methylindolizine-2-carboxamido)-
propanoate 22b
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, L-serine ethyl ester hydrochloride 15 (0.200 g,
1.18 mmol) was reacted with 5-methylindolizine-2-carboxylic acid 8b (0.100 g,
0.571 mmol) to afford ethyl (2S)-3-hydroxy-2-(5-methylindolizine-2-carboxamido)-
propanoate 22b as a yellow oil (0.072 g, 44%). Found M þ 1: 291.1374;
C15H19N2O4 requires MHþ, 291.1395. nmax(KBr)=cmꢃ1 1649 (NHC¼O) and 1732

INDOLIZINE-2-CARBOXAMIDES
2025
(C¼O); dH (400 MHz; CDCl3) 1.27 (3H, t, J 7.2 Hz, CH2CH3), 2.39 (3H, s, Ar-CH3),
4.05 (2H, d, J 3.2 Hz, OCH2), 4.24 (2H, q, J 7.2 Hz, CH2CH3), 4.85 (1H, m, NCH),
6.34 (1H, d, J 6.4 Hz, Ar-H), 6.65 (1H, m, Ar-H), 6.71 (1H, s, NH), 7.21 (1H, d, J
9.2 Hz, Ar-H), 7.24 (1H, s, Ar-H) and 7.64 (1H, s, Ar-H); dC (100 MHz; CDCl3)
14.0 (q), 18.4 (q), 55.2 (d), 61.9 (t), 63.5 (t), 98.2 (d), 111.0 (s), 111.3 (d), 117.5 (d),
118.6 (d), 122.3 (s), 133.1 (s), 133.5 (s), 165.5 (s) and 170.8 (s).
Ethyl (2S)-3-Hydroxy-2-{pyrrolo[1,2-a]quinoline-2-carboxamido}-
propanoate 22c
Following the procedure described for the synthesis of N-[2-(benzylthio)ethyl]-
indolizine-2-carboxamide 20a, L-serine ethyl ester hydrochloride 15 (0.200 g,
1.18 mmol) was reacted with pyrrolo[1,2-a]quinoline-2-carboxylic acid 8c (0.100 g,
0.47 mmol) to afford ethyl (2S)-3-hydroxy-2-{pyrrolo[1,2-a]quinoline-2-carboxami-
do}propanoate 22c as a brown oil (0.0524 g, 34.2%). Found M þ 1: 327.1348;
C18H19N2O4 requires MHþ, 327.1345. nmax(KBr)=cmꢃ1 1638 (NHC¼O) and 1732
(C¼O); dH (400 MHz; CDCl3) 1.31 (3H, t, J 7.0 Hz, CH2CH3), 3.08 (1H, br s,
OH), 4.09 (2H, m, CH2OH), 4.27 (2H, q, J 7.0 Hz, CH2CH3), 4.87 (1H, m,
NCH), 6.71 (2H, s, Ar-H), 6.91 (1H, d, J 9.6 Hz, Ar-H), 7.12 (1H, d, J 9.2 Hz,
5Ar-H), 7.17 (1H, d, J 7.2 Hz, NH), 7.26 (1H, s, OH), 7.30 (1H, t, J 7.6 Hz,
Ar-H), 7.44 (1H, t, J 7.4 Hz, Ar-H), 7.54 (1H, d, J 7.6 Hz, Ar-H), 7.78 (1H, d, J
8.0 Hz, Ar-H) and 8.30 (1H, s, Ar-H); dC (100 MHz; CDCl3) 14.1 (q), 55.2 (d),
62.0 (t), 63.7 (t), 101.0 (d), 114.2 (d), 114.4 (d), 118.7 (d), 120.4 (d), 121.8 (s),
124.0 (s), 124.6 (d), 128.2 (d), 128.6 (d), 131.3 (s), 132.8 (s), 165.1 (s) and 170.8 (s).
N-Carbomethoxymethyl-5-methylindolizine-2-carboxamide 23b
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, glycine methyl ester hydrochloride 16 (0.200 g,
1.59 mmol) was reacted with 5-methyindolizine-2-carboxylic acid 8b (0.100 g,
0.571 mmol) to afford N-carbomethoxymethyl-5-methylindolizine-2-carboxamide
23b as a brown oil (0.115 g, 81.9%). Found M þ 1: 247.1091; C13H15N2O3 requires
MHþ, 247.1083. nmax(KBr)=cmꢃ1 1649 (NHC¼O) and 1730 (C¼O); dH (400 MHz;
CDCl3) 2.46 (3H, s, OCH3), 3.78 (3H, s, Ar-CH3), 4.25 (2H, d, J 5.2 Hz, CH2),
6.39 (1H, d, J 6.4 Hz, Ar-H), 6.68–6.72 (2H, overlapping signals, Ar-H), 6.76 (1H,
br s, NH), 7.27 (1H, d, J 9.6 Hz, Ar-H) and 7.69 (1H, s, Ar-H); dC (100 MHz; CDCl3)
18.5 (q), 41.3 (t), 52.3 (q), 97.8 (d), 111.0 (d), 111.4 (d), 117.6 (d), 118.7 (d), 122.6 (s),
133.2 (s), 133.6 (s), 165.1 (s) and 170.8 (s).
N-(Carbomethoxymethyl)pyrrolo[1,2-a]quinoline-2-carboxamide 23c
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, glycine methyl ester hydrochloride 16 (0.200 g,
1.59 mmol) was reacted with pyrrolo[1,2-a]quinoline-2-carboxylic acid 8c (0.100 g,
0.47 mmol) to afford N-(carbomethoxymethyl)pyrrolo[1,2-a]quinoline-2-carboxa-
mide 23c as a brownish-yellow oil (0.094 g, 70%). Found M þ 1: 283.1083;
C16H15N2O3 requires MHþ, 283.1083. nmax(KBr)=cmꢃ1 1659 (NHC¼O) and 1733

2026
M. TUKULULA, R. KLEIN, AND P. T. KAYE
(C¼O); dH (400 MHz; CDCl3) 3.80 (3H, s, CH3), 4.27 (2H, d, J 5.2 Hz, CH2), 6.71
(1H, d, J 0.8 Hz, Ar-H), 6.75 (1H, br s, NH), 6.98 (1H, d, J 9.2 Hz, Ar-H), 7.20
(1H, d, J 9.6 Hz, Ar-H), 7.33 (1H, t, J 7.6 Hz, Ar-H), 7.48 (1H, t, J 7.6 Hz, Ar-H),
7.59 (1H, d, J 7.6 Hz, Ar-H), 7.82 (1H, d, J 8.4 Hz, Ar-H) and 8.33 (1H, s, Ar-H);
dC (100 MHz; CDCl3) 41.3 (t), 52.3 (q), 100.7 (d), 114.2 (d), 114.4 (d), 118.7 (d),
120.4 (d), 122.0 (s), 124.0 (s), 124.6 (d), 128.2 (d), 128.7 (d), 131.3 (s), 132.9 (s),
164.7 (s) and 170.9 (s).
Methyl (2S)-1-[(5-Methylindolizin-2-yl)carbonyl]pyrrolidine-2-
carboxylate 24
Following the procedure described for the synthesis of N-[2-(benzylthio)-
ethyl]indolizine-2-carboxamide 20a, L-proline methyl ester hydrochloride 17
(0.200 g, 1.20 mmol) was reacted with 5-methylindolizine-2-carboxylic acid 8b
(0.100 g, 0.571 mmol) to afford methyl (2S)-1-[(5-methylindolizin-2-yl)carbonyl]-
pyrrolidine-2-carboxylate 24 as a brown oil (0.080 g, 50%). Found M þ 1:
287.1383; C16H19N2O3 requires MHþ, 287.1396. nmax(KBr)=cmꢃ1 1603 (NC¼O)
and 1736 (C¼O); dH (400 MHz; CDCl3) 2.00 (2H, m, CH2CH2CH2), 2.13 and
2.30 (2H, 2 ꢂ m, CHCH2), 2.48 (3H, s, Ar-CH3), 3.75 (3H, s, OCH3), 3.96 (2H, m,
NCH2), 4.69 (1H, dd, J 8.2 and 5.0 Hz, CHCH2), 6.40 (1H, d, J 6.8 Hz, Ar-H),
6.68 (1H, m, Ar-H), 6.78 (1H, s, Ar-H), 7.29 (1H, t, J 9.0 Hz, Ar-H) and 7.68
(1H, s, Ar-H); dC (100 MHz; CDCl3) 18.5 (q), 25.4 (t), 28.9 (t), 49.1 (t), 52.1 (q),
59.8 (d), 99.7 (d), 110.9 (d), 112.7 (d), 117.5 (d), 118.3 (d), 122.8 (s), 132.9 (s),
165.2 (s) and 173.0 (s).
1-(Indolizin-2-yl)-7-carbomethoxy-1,9,12-trioxo-2,8,11-
triazatridecane 25
Indolizine-2-carboxylic acid 8a (0.100 g, 0.63 mmol) in dry DMF (5 ml) was
reacted with N-acetyl-glycine-lysine methyl ester acetate salt 18 (0.150 g, 0.578 mmol)
following the procedure described for the preparation of N-[4-(diethylamino)-1-
methylbutyl]indolizine-2-carboxamide 19. The crude product was purified using pre-
parative layer chromatography [on silica; elution with CH2Cl2–methanol (20:4)] to
afford 1-(indolizine-2-yl)-7-carbomethoxy-1,9,12-trioxo-2,8,11-triazatridecane 25 as
a brown solid (0.150 g, 60.1%), mp 114–116 ꢀC. Found Mþ: 402.1880; C20H26N4O5
requires M, 402.1903.
n
max(nujol)=cmꢃ1 1741 (C¼O), 1664, 1638, 1630
(3 ꢂ NHC¼O); dH (400 MHz; CDCl3) 1.40 and 1.56 (4H, 2 ꢂ m, NCH2CH2CH2),
1.76 and 1.88 (2H, 2 ꢂ m, CH2CH), 1.99 (3H, s, CH3CO), 3.36 and 3.50 (2H,
2 ꢂ m, NCH2), 3.70 (3H, s, OCH3), 3.94 (1H, dd, J 16.8 and 4.8 Hz, NCHaCO)
and 4.05 (1H, dd, J 16.8 and 5.6 Hz, NCHbCO), 4.47 (1H, m, CH2CH), 6.50 (1H,
t, J 6.8 Hz, Ar-H), 6.16 (1H, br s, NH), 6.64–6.69 (2H, overlapping signals,
Ar-H), 6.89 (1H, m, NH), 7.30 (1H, d, J 8.8 Hz, Ar-H), 7.41 (1H, d, J 7.2 Hz,
NH), 7.85 (1H, s, Ar-H) and 7.90 (1H, d, J 6.8 Hz, Ar-H); dC (100 MHz; CDCl3)
22.0 (t), 22.9 (q), 29.1 (t), 30.8 (t), 38.3 (t), 43.1 (t), 52.2 (q), 52.4 (d), 97.1 (d),
111.9 (d), 114.3 (d), 118.4 (d), 119.7 (d), 123.3 (s), 125.6 (d), 132.9 (s), 165.6 (s),
169.2 (s), 170.8 (s) and 172.5 (s).

INDOLIZINE-2-CARBOXAMIDES
2027
ACKNOWLEDGMENTS
We are grateful to the National Research Foundation (NRF: GUN 2069255)
for a bursary (M. T.) and to the NRF, the Medical Research Council of South
Africa, and Rhodes University for generous financial support. Any opinions, find-
ings, and conclusions or recommendations expressed in this material are those of
the authors and therefore the NRF does not accept any liability.
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