Manganese(III)-mediated radical cyclisations for the (Z)-selective synthesis of exo-alkylidene pyrrolidinones and pyrrolidines

Article abstract of DOI:10.1039/c2cc32382f

The cyclisation of alkynyl amido- and amino-malonates in the presence of manganese(iii) acetate gives exo-alkylidene pyrrolidinones and pyrrolidines with a preference for the (Z)-alkene product isomer.

Full text of DOI:10.1039/c2cc32382f

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 6496–6498
www.rsc.org/chemcomm
COMMUNICATION
Manganese(III)-mediated radical cyclisations for the (Z)-selective
synthesis of exo-alkylidene pyrrolidinones and pyrrolidinesw
Harriet A. Keane, Wilfried Hess and Jonathan W. Burton*
Received 2nd April 2012, Accepted 8th May 2012
DOI: 10.1039/c2cc32382f
The cyclisation of alkynyl amido- and amino-malonates in the
presence of manganese(III) acetate gives exo-alkylidene pyrroli-
dinones and pyrrolidines with a preference for the (Z)-alkene
product isomer.
Based on this precedent, we proposed that cyclisation of an
appropriately substituted malonyl radical 4 derived from 3,
onto an alkyne would deliver the corresponding alkenyl
radical 5 which would likely exist as an equilibrating mixture
of (E) and (Z)-isomers (Scheme 2).11 We surmised that using a
suitably bulky alcohol might result in H-atom abstraction
occurring more readily from the (Z)-adduct radical, (Z)-5, to
give the (Z)-alkylidene pyrrolidinone, (Z)-6, selectively giving
a complementary methodology to our zinc(II) and Hatakeyama’s
indium(III)-catalysed methodology for the formation of
(E)-alkylidene pyrrolidines/pyrrolidinones.12
Pyrrolidines and pyrrolidinones are important heterocyclic
structural motifs that are present in many ligands, are used in
the field of organocatalysis and found in a wide variety of natural
products. Inspired by the indium(III)-catalysed Conia-ene reac-
tion of alkynyl a-aminomalonates described by Hatakeyama1
and co-workers, we recently reported the use of zinc(II) halides
for the exo (and endo) cyclisation of alkynyl a-aminomalonates
to give (E)-alkylidene pyrrolidines and pyrrolidinones with high
selectivity.2–4 Herein we describe a complementary method for
the synthesis of (Z)-alkylidene pyrrolidinones and pyrrolidines
from alkynyl a-aminomalonates.
As a starting point, we investigated the cyclisation of the
terminal alkyne substrates 7.13 Exposure of the amidomalonates
7a14 and 7b to manganese(III) acetate in ethanol at reflux6,7,12
delivered the corresponding exo-methylene pyrrolidinones
8a and 8b in 67% and 74% yield respectively (Scheme 3).
Encouragingly, no trace of product arising from 6-endo-dig
We,5 and others,6,7 have shown that alkenyl malonates can
be converted into cyclopentanes and [3.3.0]-bicyclic g-lactones
on exposure to manganese(III) acetate8 and an appropriate
copper(II) salt9 and we have applied this oxidative radical
methodology in the total synthesis of a cyclopentane-containing
natural product.10 With acetylenic substrates, however,
reduction of the vinylic adduct radical tends to occur by
H-atom abstraction from solvent.7 Snider has previously shown
that exposure of the alkynyl acetoacetate 1 to manganese(III)
acetate in ethanol gives rise to the alkylidene cyclopentanones 2
in 66% yield with modest (E)-selectivity (Scheme 1).7
Scheme 2 Mechanistic hypothesis for formation of (Z)-alkylidene
pyrrolidinones.
Scheme 1 Cyclisation of alkynyl acetoacetate 1 reported by Snider.7
Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: jonathan.burton@chem.ox.ac.uk; Fax: +44 (0)1865 285002
w Electronic supplementary information (ESI) available: experimental
details, characterisation data and NMR spectra of new compounds.
See DOI: 10.1039/c2cc32382f
Scheme 3 Cyclisation of terminal acetylene substrates.
c
6496 Chem. Commun., 2012, 48, 6496–6498
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 1 Cyclisation of internal alkyne substrates16
Table 2 Screening of various alcohols as H-atom donors16
Entry
R
T
Time
Product
Yield (%)
E/Z
Entry
Solvent
T/1C
t (h)
Yield (%)
E/Z
1
Me
Me
Me
Et
nPr
nBu
Ph
80 1C
RT
80 1C
RT
RT
15 h
15 min
15 h
2 h
2 h
15 h
2 h
10a
10a
10a
10b
10c
10d
10e
78
75
68
86
72
73
65
1 : 3.8
1 : 3.9
1 : 1.8
1 : 4.7
1 : 2.9
1 : 3.0
1 : 3.0
1
2
3
4
5
6
EtOH
80
80
80
80
20
20
15
15
15
15
2
73
78
75
85
78
51
1 : 3.0
1 : 3.0
1 : 4.5
1 : 2.0
1 : 3.0
1 : 6.0
2
PentOH
iPrOH
BnOH
EtOH
3a
4
5
6
7
80 1C
RT
iPrOH
3
a
Reaction was conducted in acetonitrile.
product being formed with only approximately 1 : 3 (E) : (Z)
selectivity along with numerous by-products.17 In terms of
substrate generality and maximising the yield of (Z)-exo-
alkylidene pyrrolidinones, ethanol is the best initial solvent
choice for these reactions with subsequent substrate-specific
solvent optimisation potentially allowing improved (Z)-selectivity.
Using ethanol as the solvent, we next briefly investigated the
substrate scope for the formation of pyrrolidines and pyrro-
lidinones (Table 3). It was anticipated that increasing the bulk
of the esters should lead to higher amounts of the (Z)-exo-
alkylidene pyrrolidinone. We compared the cyclisations of the
diethyl (9d), dibenzyl (11) and dit-butyl (13) malonates
(Table 3, entries 1–3). As expected, increasing the size of the
malonic esters gave the product exo-alkylidene pyrrolidines
with increased (Z)-selectivity (Table 3, entries 1–3).
cyclisation was detected in the crude 1H NMR spectrum
neither was there any trace of the thermodynamically more
favoured a,b-unsaturated g-lactams derived from conjugation
of the olefinic double bond in 8. Given this encouraging initial
result we moved to examine the cyclisation of internal alkyne
substrates 9 (Table 1).
Cyclisation of the internal alkyne 9a at 80 1C in ethanol gave
the exo-alkylidene pyrrolidinone 10a in 78% yield as a 1 : 3.8
mixture of alkene isomers pleasingly with the (Z)-geometrical
isomer predominating15 and in contrast to the cyclisation of 1
reported by Snider.7 We found that these cyclisations could be
conducted at room temperature in 2 h or less (Table 1, entries 2,
4, 5 and 7). The geometrical integrity of the (Z)-alkene 10d was
preserved on re-exposure to the reaction conditions indicating
that the product diastereocontrol is likely the result of kineti-
cally controlled hydrogen abstraction by the equilibrating
adduct radicals 5. The use of acetonitrile resulted in the product
being isolated with similar yield but with reduced diastereo-
control (Table 1, entry 3). The ethyl, propyl and butyl-
substituted alkynes behaved similarly to the methyl substituted
alkyne 9a giving the corresponding exo-alkylidene pyrrolidinones
in 72–86% yield and up to 4.7 : 1 (Z):(E)-selectivity (Table 1,
entries 4–6). The phenylacetylene 9e also underwent cyclisation to
give the corresponding exo-arylidene pyrrolidinone 10e in 65%
yield and 3 : 1 (Z):(E)-selectivity (Table 1, entry 7).
We also investigated the synthesis of pyrrolidines by the
cyclisation of N-carbamoyl-protected alkynyl malonates 15
(Table 3, entries 4–6).13 These substrates 15 underwent cycli-
sation under our standard reaction conditions to give the
corresponding alkylidene pyrrolidines 16 in 69–78% yield.
The internal alkyne 15c gave the product 16c with 2.8 : 1
(Z) : (E) selectivity.
Not only are these cyclisations applicable to the formation
of 5-membered rings but it is also possible to synthesise
piperidinones. Thus, exposure of the alkynyl malonates 17a
and 17b to manganese(III) acetate in ethanol at 80 1C gave the
corresponding piperidinones 18a and 18b in 66% and 71%
yields respectively (Scheme 4).16
The results reported in Table 1 were encouraging in that the
pyrrolidinones 10 were formed in synthetically useful yields
with moderate diastereocontrol. We therefore decided to
investigate the influence of different alcohols as hydrogen
atom donors. With the butyl-substituted alkyne 9d, moving
from ethanol to n-pentanol (PentOH) resulted in the product
10d being isolated in 78% yield with the same selectivity
(Z)-selectivity (Table 2, entries 1 and 2). Moving to a consider-
ably more hindered alcohol, iso-propanol, resulted in full
conversion with formation of the product 10d in 75% yield
but with improved (Z)-selectivity (Table 2, entry 3). The use of
benzyl alcohol as solvent resulted in the product being formed
in 85% yield but with reduced (Z)-selectivity (Table 2, entry 4).
Using iso-propanol as solvent, and reducing the reaction temp-
erature resulted in the product 10d being formed with improved
(Z)-selectivity albeit in reduced yield (Table 2, entry 6).17
Unfortunately, using the same conditions with the phenyl-
substituted acetylene 9e (iso-propanol, 20 1C) resulted in the
In conclusion we have developed a mild and efficient
manganese(III)-mediated cyclisation reaction of alkynoic
amidomalonates and protected aminomalonates. This provides
Table 3 Substrate scope16,18
Entry R1 R2 R3
Substrate
Product Yield (%) E/Z
1a
2b
3a
4a
5b
6b
nBu Et Bn
nBu Bn Bn
nBu tBu Bn
9d, X = O
11, X = O
13, X = O
10d
12
14
73
79
82
78
78
69
1 : 3.0
1 : 3.5
1 : 6.6
—
—
1 : 2.8
H
H
Et CO2Bn 15a, X = H2 16a
tBu CO2Et 15b, X = H2 16b
nBu Et CO2Et 15c, X = H2 16c
a
b
Reaction was conducted at 80 1C. Reaction was conducted at RT.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6496–6498 6497

View Article Online
6459–6463; (o) S. Cacchi, G. Fabrizi and E. Filisti, Org. Lett.,
2008, 10, 2629–2632; (p) E. Dumez, A. C. Durand, M. Guillaume,
P. Y. Roger, R. Faure, J. M. Pons, G. Herbette, J. P. Dulcere,
D. Bonne and J. Rodriguez, Chem.–Eur. J., 2009, 15, 12470–12488;
(q) S. Yamazaki, S. Morikawa, K. Miyazaki, M. Takebayashi,
Y. Yamamoto, T. Morimoto, K. Kakiuchi and Y. Mikata, Org.
Lett., 2009, 11, 2796–2799.
5 L. H. Powell, P. H. Docherty, D. G. Hulcoop, P. D. Kemmitt and
J. W. Burton, Chem. Commun., 2008, 2559–2561.
6 B. B. Snider and B. A. McCarthy, J. Org. Chem., 1993, 58,
6217–6223.
Scheme 4 Synthesis of exo-alkylidene piperidinones.
a convenient and practical entry into the synthesis of (Z)-exo-
alkylidene pyrrolidinones and pyrrolidines respectively. The
products can be obtained in good yields with a clear preference
for the sterically more demanding (Z)-products, rendering the
approach complementary to previously developed Conia-ene
type reactions.1,2
7 B. B. Snider, J. E. Merritt, M. A. Dombroski and B. O. Buckman,
J. Org. Chem., 1991, 56, 5544–5553.
8 For reviews of manganese(III) acetate in organic synthesis see:
(a) B. B. Snider, Chem. Rev., 1996, 96, 339–363; (b) G. G.
Melikyan, Org. React., 1997, 49, 427–675; (c) A. S. Demir and
M. Emrullahoglu, Curr. Org. Synth., 2007, 4, 321–351;
J. W. Burton, in Encyclopedia of Radicals in Chemistry, Biology
and Materials, ed. C. Chatgilialoglu and A. Studer, John Wiley &
Sons Ltd, Chichester, UK, 2012, pp. 901–942.
We thank the European Commission (FP7-PEOPLE-2009-
IEF-254038) for financial support. We thank the analytical
sections of our Department for their excellent support.
9 The use of cerium(IV) ammonium nitrate and copper(II) nitrate in
acetic acid has also been used to synthesis g-lactones from pentenyl
malonates see: E. Baciocchi, A. B. Paolobelli and R. Ruzziconi,
Tetrahedron, 1992, 48, 4617.
10 J. J. Davies, T. M. Krulle and J. W. Burton, Org. Lett., 2010, 12,
2738–2741.
Notes and references
1 K. Takahashi, M. Midori, K. Kawano, J. Ishihara and
S. Hatakeyama, Angew. Chem., Int. Ed., 2008, 47, 6244–6246.
2 W. Hess and J. W. Burton, Adv. Synth. Catal., 2011, 353, 2966–2970.
3 We have also developed a Pd-catalysed synthesis of alkylidene
pyrrolidines see: W. Hess and J. W. Burton, Chem.–Eur. J., 2010,
16, 12303–12306.
11 R. W. Fessenden and R. H. Schuler, J. Chem. Phys., 1963, 39,
2147–2195.
12 For previous work on the synthesis of exo-methylene pyrrolidi-
nones by manganese(III)-mediated cyclisation of appropriately
substituted b-keto carboxamides see: ref. 4a,e.
4 For the synthesis of 5-membered nitrogen and oxygen heterocycles
by the cyclisation of enols/enolates onto electronically neutral
acetylenes see ref. 1–3 and: (a) J. Cossy and C. Leblanc, Tetra-
hedron Lett., 1989, 30, 4531–4534; (b) X. Marat, N. Monteiro and
G. Balme, Synlett, 1997, 845–847; (c) B. Clique, N. Monteiro and
G. Balme, Tetrahedron Lett., 1999, 40, 1301–1304; (d) E. Dumez,
J. Rodriguez and J. P. Dulcere, Chem. Commun., 1997, 1831–1832;
(e) J. Cossy, A. Bouzide and C. Leblanc, J. Org. Chem., 2000, 65,
7257–7265; (f) M. Woods, N. Monteiro and G. Balme, Eur. J. Org.
Chem., 2000, 1711–1718; (g) B. Clique, S. Vassiliou, N. Monteiro
and G. Balme, Eur. J. Org. Chem., 2002, 1493–1499;
(h) M. Guillaume, E. Dumez, J. Rodriguez and J. P. Dulcere,
Synlett, 2002, 1883–1885; (i) M. Cavicchioli, X. Marat,
N. Monteiro, B. Hartmann and G. V. Balme, Tetrahedron Lett.,
2002, 43, 2609–2611; (j) S. Azoulay, N. Monteiro and G. Balme,
Tetrahedron Lett., 2002, 43, 9311–9314; (k) G. Liu and X. Lu,
Tetrahedron Lett., 2003, 44, 467–470; (l) M. Nakamura,
C. G. Liang and E. Nakamura, Org. Lett., 2004, 6, 2015–2017;
(m) S. Morikawa, S. Yamazaki, Y. Furusaki, N. Amano, K. Zenke
and K. Kakiuchi, J. Org. Chem., 2006, 71, 3540–3544;
(n) S. Morikawa, S. Yamazaki, M. Tsukada, S. Izuhara,
T. Morimoto and K. Kakiuchi, J. Org. Chem., 2007, 72,
13 The amidomalonates were readily prepared according to the
method of Hatakeyama see ref. 1.
14 The amidomalonate 7a undergoes cyclisation on exposure to
mildly acidic conditions during silica gel chromatography. Cyclisa-
tion of the N-PMB dimethyl malonate analogue of 7a under
indium(III) catalysis has previously been reported by Hatakeyama.
Additionally cyclisation of a closely related amidomalonate on
silica gel has also been observed by Hatakeyama, see ref. 1.
15 Cyclisation of 9a under zinc(II) catalysis gives 10a with high
(E)-selectivity see ref. 2. Hatakeyama has reported cyclisation of
a closely related substrate under indium(III) catalysis see ref. 1.
16 The stereochemistry of the products was assigned on the basis of
1H NMR NOE experiments. The (E) : (Z) ratios were measured by
1H NMR.
17 The reactions conducted in iso-propanol at room temperature
resulted in complete conversion, however, numerous by-products
were also formed.
18 The stereochemistry of 12 and 14 was assigned by NMR comparison
with the other products reported in the paper.
c
6498 Chem. Commun., 2012, 48, 6496–6498
This journal is The Royal Society of Chemistry 2012