2
Journal of Chemical Research 00(0)
N
O
O
OH
N
N
NH2
O
O
N
HN
NH
O
O
O
O
Et
O
N
1
HO
2
3
N
Ph
Figure 1. Biologically active indolizine derivatives.
involving base-mediated cyclisation of 1-substituted- method to access indolizine-2-carboxamides using more
11
2
-methylpyridinium salts. The application of Morita– complex and medicinally interesting amines proved unsuc-
Baylis–Hillman (MBH) methodology in the synthesis of cessful. Following further exploratory, but unsuccessful
1
2,13
indolizines was first reported by our group
and, in this studies, involving the use of organoboron catalysts (boric
communication, we now report the use of this approach in acid, trimethyl borate, phenylboronic acid and tris(2,2,2-
the preparation of a range of indolizine-2-carboxamido trifluoroethyl) borate), attention was turned to the use of
derivatives and the evaluation of their anti-malarial, anti- propylphosphonic acid anhydride (T3P) − a coupling agent
trypanosomal and anti-tuberculosis potential and their that has found use in a range of multi-component transfor-
2
0
HIV-1 protease (PR) and integrase (IN) inhibition activity. mations, including the amidation of carboxylic acids.
Examination of the efficacy of this reagent, by varying the
base, the solvent, the temperature and the work-up proto-
col, finally permitted the synthesis, albeit in no more than
Results and discussion
In the synthesis of the critical indolizine-2-carboxylic acids modest yields, of novel carboxamides from reactions of the
and 10 (Scheme 1), a step-wise approach was initially indolizine-2-carboxylic acids 9 and 10 with a series of
adopted, in which thermal cyclisation is facilitated by prior amines as outlined in Scheme 2. These amines included:
9
1
4
acetylation of the MBH adduct 5. Such acetylation has phenylhydrazine and hydrazine to afford compounds 11a,b
been achieved either by refluxing the adduct in acetic anhy- and 13b as analogues of isoniazid, an anti-tuberculosis
2
1
dride for 30min or by treating the adduct with acetyl chlo- drug to which resistance has emerged; compounds con-
2
2
23
ride in the presence of pyridine at room temperature. taining the medicinally significant pyridinyl, furfuryl
2
4
However, we found that prior acetylation and isolation of and thiazolyl moieties, namely, 2-(2-pyridinyl)ethyl-
the acetylated adduct 7 is not necessary, and that the amine, furfurylamine, 2-aminothiazole and 2-aminopyri-
indolizine-2-carboxylate esters 7 and 8 may be generated dine to afford the N-substituted carboxamides 11c, 11e, 12f
efficiently by refluxing a mixture of the MBH adduct 5 in and 12g, respectively; and benzylamine, leading to
1
2,15
acetic anhydride in a one-pot approach.
ing co-formation of both the desired product 7 and its that the indolizine-2-carboxamides 11d and 11e were
-acetylated analogue 8 was simply avoided by controlling obtained from 3-acetylindolizine-2-carboxylic acid 10, the
The complicat- N-benzylindolizine-2-carboxamide 11d. It should be noted
3
the reaction time. Thus, treatment of the MBH adduct 5 reactions proceeding with a de-acetylation step. While the
with refluxing Ac O for 2days yielded methyl indolizine- yields were variable and the products subject to decomposi-
2
1
6
2
-carboxylate 7 in 93% yield, while extending the reac- tion, nuclear magnetic resonance (NMR) and high-resolu-
tion time to 7days afforded the 3-acetylated analogue 8, in tion mass spectra (HRMS) analyses permitted their
3% yield. unambiguous characterisation, with infrared (IR) data con-
The indolizine-2-carboxylic acids 9 and 10, the critical firming the presence of the required NH and the amide
8
precursors for the amidation studies, were obtained by C=O absorption bands. Other researchers have observed
base-catalysed hydrolysis of the respective esters 7 and 8. inherent instability and lack of reactivity in certain
2
5,26
Indolizine-2-carboxylic acid 9 was obtained as yellow crys- indolizine derivatives.
tals in 86% yield, the 3-acetoxy analogue 10 in up to 93% Indolizines have been reported to exhibit a wide range of
2
7
yield, contaminated in some cases with the non-acetylated biological activities, including anti-mycobacterial and
acid 9 – an observation attributed to competitive, sequential anti-HIV-1 activity.28,29 Preliminary assessments of the bio-
de-acylation and saponification steps.
logical activity of indolizine-2-carboxamide derivatives
the inability to gen- prepared in this study against HIV-1 IN and HIV-1 PR,
1
2,13,17
In earlier studies in our group,
erate the acid chloride of indolizine-2-carboxylic acid malaria, trypanosomiasis and tuberculosis were under-
prompted the use of 1,1′-carbonyldiimidazole (CDI) as a taken. While none of these compounds showed toxicity
couplingagent, whichpermittedtheformationofindolizine- against Human Embryonic Kidney 293 (HEK 293) cells at
2
-carboxamides from the acid 9 and aliphatic amines in a concentration of 20 µM, their activity in the other assays
1
8,19
good yields.
However, attempted application of this proved to be generally disappointing. The carbohydrazide