A novel synthesis of 2,3-dihydro-7(1H)-indolizinones

Article abstract of DOI:10.1016/S0040-4039(00)00406-8

Intramolecular coupling reactions of enynes 2-[1-(2-propynyl)tetrahydro- 2H-pyrrol-2-yliden]acetonitrile (10) and ethyl 2-[1-(2-propynyl)tetrahydro- 2H-pyrrol-2-ylidene]acetate (11), using 9-BBN, catecholborane and alkaline silver nitrate, afforded the 2,3-dihydro-7(1H)-indolizinones, 7-oxo-1,2,3,7- tetrahydro-8-indolizinecarbonitrile (5) and ethyl 7-oxo-1,2,3,7-tetrahydro-8- indolizinecarboxylate (6), respectively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00406-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3497–3500
A novel synthesis of 2,3-dihydro-7(1H)-indolizinones
David Gravestock ∗ and Ian G. Peirson
School of Chemical and Physical Sciences, University of Natal, Private Bag X01, Scottsville, Pietermaritzburg, 3209,
South Africa
Received 9 February 2000; accepted 7 March 2000
Abstract
Intramolecular coupling reactions of enynes 2-[1-(2-propynyl)tetrahydro-2H-pyrrol-2-ylidene]acetonitrile (10)
and ethyl 2-[1-(2-propynyl)tetrahydro-2H-pyrrol-2-ylidene]acetate (11), using 9-BBN, catecholborane and alkaline
silver nitrate, afforded the 2,3-dihydro-7(1H)-indolizinones, 7-oxo-1,2,3,7-tetrahydro-8-indolizinecarbonitrile (5)
and ethyl 7-oxo-1,2,3,7-tetrahydro-8-indolizinecarboxylate (6), respectively. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: 2,3-dihydro-7(1H)-indolizinones; dihydro-γ-pyridones; Eschenmoser coupling reaction; enynes; enaminones.
Relatively few methods for constructing 2,3-dihydro-7(1H)-indolizinones (1) (also referred to as
dihydro-γ-pyridones) have been reported.1 Danishefsky reported the synthesis of iso-A58365A (4), an
isomer of the angiotensin converting enzyme inhibitor, A58365A (3) by annulation of diazomethylvinyl-
ketone with a secondary thiolactam.1 In contrast, methods for constructing the reduced version of this
ring system, namely 2,3,5,6-tetrahydro-7(1H)-indolizinone (2), abound.2
We now report the synthesis of two 2,3-dihydro-7(1H)-indolizinones, 7-oxo-1,2,3,7-tetrahydro-8-
indolizinecarbonitrile (5) and ethyl 7-oxo-1,2,3,7-tetrahydro-8-indolizinecarboxylate (6), by means of
∗
Corresponding author. Tel: 0027 33 260 5325; fax: 0027 33 260 5009; e-mail: gravestockd@chem.unp.ac.za (D. Gravestock)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00406-8
tetl 16686

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an intramolecular coupling reaction of boranes derived from enynes 2-[1-(2-propynyl)tetrahydro-2H-
pyrrol-2-ylidene]acetonitrile (10) and ethyl 2-[1-(2-propynyl)tetrahydro-2H-pyrrol-2-ylidene]ethanoate
(11), respectively.
The strategy communicated in this letter represents a new route to this ring system. This strategy is
summarised in Scheme 1.
Scheme 1. Reagents and conditions: (i) NaH, propargyl bromide, THF, rt, 85%; (ii) P2S5, Na2CO3, THF, rt, 87%; (iii) BrCH2Z,
CH3CN, rt, then Et3N, Ph3P, rt, 30–74%; (iv) 9-BBN, catecholborane, 0°C, then 2 M aq. KOH, 5 M aq. AgNO3, rt, 12–19%
Thiolactam 9 was prepared in two steps from 2-pyrrolidinone (7). The first step involved alkylation of
2-pyrrolidinone (7) with propargyl bromide. 1-(2-Propynyl)tetrahydro-2H-pyrrol-2-one (8) was obtained
in a satisfactory 85% yield. Thionation of this substrate using a mixture of phosphorus pentasulfide and
sodium carbonate3 afforded 1-(2-propynyl)tetrahydro-2H-pyrrole-2-thione (9) in 87% yield. The key
enaminones (10, 11 and 12) were prepared by Eschenmoser sulfide contraction4 of thiolactam (9) with
bromoacetonitrile, ethyl bromoacetate and phenacyl bromide, respectively. 2-[1-(2-Propynyl)tetrahydro-
2H-pyrrol-2-ylidene]acetonitrile (10), ethyl 2-[1-(2-propynyl)tetrahydro-2H-pyrrol-2-ylidene]ethanoate
(11) and 1-phenyl-2-[1-(2-propynyl)tetrahydro-2H-pyrrol-2-ylidene]-1-ethanone (12) were obtained in
74, 30 and 60% yield, respectively. The enaminones were obtained as predominantly one geometric
isomer based on GC evidence of the material before column chromatography. Comparison of 1H NMR
data with literature values showed that these compounds were obtained as the E-isomers (vide infra).
The preferred geometry of these types of enaminones appears to depend on whether the nitrogen atom
is secondary or tertiary. Secondary enaminones have been shown to exist in the cis-s-cis configuration
which allows intramolecular hydrogen bonding resulting in a very stable six-membered ring.5,6 Tertiary
enaminones were shown to exist in the trans-s-trans conformation by Michael.7 This was demonstrated
by the anisotropic deshielding effect that the carbonyl oxygen atom of vinylogous urethanes has, due to
its spatial proximity, on the hydrogen atom at C-3 of the pyrrolidine ring.
A related vinylogous nitramine (15) was prepared in 43% yield according to the route shown in Scheme
2. This involved methylation of thiolactam (9) on sulfur followed by condensation of the resulting
methylthioiminium salt (14) with nitromethane.

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Scheme 2. Reagents and conditions: (i) CH3I, CHCl3; (ii) CH3NO2, K2CO3, DMF, 43%
Brown and Coleman communicated a route to acetylenic organoboranes and alcohols by chemoselec-
tive hydroboration of double bonds in the presence of triple bonds by 9-BBN.8 It is known that 9-BBN is
exceptionally sluggish in the hydroboration of terminal alkynes relative to other dialkylboranes.8 In addi-
tion, hydroboration of acetylenes with 9-BBN is slow compared to hydroboration of structurally similar
olefins. Brown et al. reported the very ready coupling of hydroborated olefins in situ by silver nitrate in the
presence of alkali.9,10 Catecholborane is known to be far less reactive than dialkylboranes11,12 but is well
known to monohydroborate alkynes to form the corresponding alkeneboronic esters.13 Consideration of
these facts prompted our investigation to assess whether the above methodology could be used to cyclise
enynes 10–12 and 15.
The cyclisation reactions were effected by adding catecholborane followed by 9-BBN to the enynes
in THF at 0°C and subsequent treatment with 5 M aqueous silver nitrate and 2 M aqueous sodium
hydroxide solution.14 The cyclisation reaction failed if only catecholborane or 9-BBN was used. In
this manner, 7-oxo-1,2,3,7-tetrahydro-8-indolizinecarbonitrile (5) and ethyl 7-oxo-1,2,3,7-tetrahydro-
8-indolizinecarboxylate (6) were synthesised in 19 and 12% yield, respectively.15 Little appears to be
known of the behaviour of enaminones and related compounds toward hydroboration and merits further
investigation. Based on the literature precedent presented (vide supra), it appears reasonable to assume
that the carbon–carbon double bond and triple bond are hydroborated with 9-BBN and catecholborane,
respectively. The cyclisation reaction then presumably results from alkaline silver nitrate mediated
intramolecular coupling of the derived alkylborane and vinylborane.
The cyclisation reaction is clearly dependent on the nature of the electron-withdrawing group Z
(Scheme 1). Vinylogous enaminone 12 and nitramine 15 failed to give cyclised products 16 and 17
under the given reaction conditions.
In summary, we have developed a new method for the synthesis of the 2,3-dihydro-7(1H)-indolizinone
ring system. These compounds are attractive intermediates for the preparation of more complex natural
products. Attempts to extend the methodology to 6,7,8,9-tetrahydro-2H-quinolizin-2-ones are in pro-
gress.
Acknowledgements
We thank the University of Natal, Pietermaritzburg, for providing funding for this research.

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14. Typical experimental procedure: A stirred solution of the enyne (100–150 mg) in dry THF (5–10 cm3) was cooled to
0°C and then treated with 9-BBN (1 mol equivalent, 0.5 M solution in THF). After 120 minutes catecholborane (1 mol
equivalent, 1.0 M solution in THF) was added at 0°C and the resulting mixture stirred for 60 min and allowed to warm
to ambient temperature. An aqueous potassium hydroxide solution (2 M, 2 mol equivalents) was added at 0°C followed
by an aqueous silver nitrate solution (5 M, 2 mol equivalents). The resulting mixture was allowed to warm to ambient
temperature and stirred for 60 min. The reaction mixture was diluted with water and the organic material extracted with
ethyl acetate (5×10 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by
column chromatography (SiO2, 50–60% ethyl acetate/hexane) to afford the desired products in yields of 12–19%.
15. All new compounds were characterised spectroscopically and by high resolution mass spectrometry.