Combination iminium, enamine and copper(i) cascade catalysis: A carboannulation for the synthesis of cyclopentenes

Article abstract of DOI:10.1039/b802416b

A one-pot, multistep reaction cascade to cyclopentenes from α,β-unsaturated ketones and propargylated carbon acids through a combination of organocatalysis and transition metal ion catalysis is reported; the reaction cascade is simple to perform, occurs u

Full text of DOI:10.1039/b802416b

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Combination iminium, enamine and copper(I) cascade catalysis:
a carboannulation for the synthesis of cyclopentenesw
Ting Yang,a Alessandro Ferrali,a Leonie Campbellb and Darren J. Dixon*a
Received (in Cambridge, UK) 12th February 2008, Accepted 31st March 2008
First published as an Advance Article on the web 21st April 2008
DOI: 10.1039/b802416b
A one-pot, multistep reaction cascade to cyclopentenes from a,b-
unsaturated ketones and propargylated carbon acids through a
combination of organocatalysis and transition metal ion cata-
lysis is reported; the reaction cascade is simple to perform,
occurs under mild conditions and is broad in scope.
simultaneous metal ion activation of alkynes, could be com-
bined in a cascade sequence constituting a new carbo-
annulation method to cyclopentenes. More specifically, we
envisaged that iminium ion activation of a,b-unsaturated ke-
tone 1 to intermediate 5 through condensation with a suitable
amine organocatalyst 2 could promote Michael addition of
alkyne tethered malonate pro-nucleophile 3 via its conjugate
base 6.6 Bond formation should lead directly to intermediate
enamine 7 where the a-carbon is nucleophilic and poised to
attack adjacent reactive electrophiles. If this electrophile was
indeed an alkynyl functional group activated by metal ion
complex 4 then intramolecular carbon–carbon bond formation
was anticipated, resulting in an intermediate such as 9.7 Proto-
nolysis and hydrolysis would then release the catalysts and the
carbocyclic product 10.8 With many points of diversity present
in the reaction products, this cascade sequence would be a
powerful method for both cyclopentene library generation and
target synthesis (Scheme 1). Herein we present our findings.
Proof of principle studies were carried out using cyclohexenone
11 (1 eq.) and dimethyl propargylmalonate 12 (1.5 eq.) as test
substrates (Table 1). Methanol was adopted as the initial solvent
owing to its widespread employment in iminium activation of a,b-
unsaturated carbonyl compounds.3b,4,9 Pyrrolidine (20 mol%) was
selected as the initial organocatalyst owing to its superior perfor-
mance in a range of previously reported organocatalytic reac-
tions.10 With two variables fixed, a range of transition metal salts
or complexes [Cu(OTf)2–PPh3, AgOTf–PPh3, Hg(OTf)2–PPh3,
The desire for practically simple and synthetically efficient
organic transformations has led to the development of many
innovative strategies, concepts and methodologies. One ap-
proach is to employ reaction cascades; these can be syntheti-
cally powerful allowing rapid and efficient syntheses of
complex molecules from relatively simple starting materials
by enabling several bond-forming events to occur in the same
reaction vessel. Such multistep sequences significantly reduce
the drain of resources associated with one-reaction, one-pot
approaches. Whereas a myriad of elegant cascade sequences
catalysed by a single chemical entity1 have been described, far
fewer reports exist on the use of a combination of more than
one mutually compatible catalysts for reaction sequences.2
Over the past few years a significant number of cascades
involving (single or multiple) amine-based organocatalysts
have been reported.3 These catalysts have allowed the union
of multiple reactive functionalities such as electron poor
alkenes, aldehydes, ketones, imines, nitroalkanes, and other
pro-nucleophiles by providing two key activation modes:
iminium activation of a,b-unsaturated carbonyl compounds
and enamine activation of carbonyl compounds.4 These two
modes in combination have facilitated some incredibly elegant
transformations of relatively simple starting materials to
complex stereochemically defined molecular architectures.
Likewise, the field of transition metal or transition metal ion
catalysed cascade sequences continues to mature and develop.
One area in particular that has witnessed significant interest
over the past decade is that of additions to alkyne function-
ality.5 More specifically, cascade reactions involving alkyne
functionality, wherein ‘soft’ transition metal ions are employed
to provide the necessary activation to trigger the process.5f
Confident that mutually compatible cyclic secondary amine
organocatalysts and suitably ligated transition metal ion com-
plexes could be identified, we proposed that iminium activation
of a,b-unsaturated ketones, enamine activation of ketones and
a School of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Darren.Dixon@man.ac.uk;
Fax: +44 (0)161 2754939; Tel: +44 (0)161 2751426
b AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK
SK10 4TG
w Electronic supplementary information (ESI) available: Experimental
procedures, 31P NMR studies and spectral data for compounds 16–29
and 31. See DOI: 10.1039/b802416b
Scheme 1 Concept of the combined iminium, enamine and metal ion
catalysis cascade to cyclopentenes.
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Table 1 Proof of principle, catalyst identification and reaction optimisation studies
Entry
Metal salt
Amine
Solvent
16 (%)a
13 (%)a
11 (%)a
1
2
3
Cu(OTf)2
AgOTf
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Piperidine
n-Propylamine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
—
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CHCl3
Toluene
THF
91
80
32
86
71
21
13
35
27
21
9
0
0
—
0
0
18
0
0
0
16
0
8
0
0
0
0
0
16
22
27
38
48
63
25
Hg(OTf)2
Au(PPh3)Cl, AgOTf
Pd(PPh3)4
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
4b
5b
6
7
8
9
10
11
12
MeOH
0
b
a 1H NMR yield measured using an internal standard. Additional PPh3 (20 mol%) was not added to the reaction mixture.
Au(PPh3)Cl–AgOTf and Pd(PPh3)4] was screened for perfor-
mance in the cascade at room temperature for 24 h. In each
reaction ps-BEMP (10 mol%) was added to quench any residual
protic acids present in the commercial metal ion salts.5f,11 The
results are presented in Table 1 (entries 1–5).
probing changes to the a,b-unsaturated ketone and the pro-
nucleophile (Scheme 2). A methyl substituent was tolerated at
the g, d, and e positions of the cyclohexenone Michael
acceptor and high diastereoselectivity was observed in the
formation of 17. Cycloheptenone and cyclopentenone gave
rise to the 7,5- and 5,5-bicyclic ring systems respectively.
Interestingly, in the latter case a mixture of isomeric alkene
products 21a–c was isolated, with the major being the non-
conjugated endocyclic alkene. Methyl and ethyl vinyl ketones
gave rise to the respective monocyclic cyclopentenes 22 and 23.
Likewise longer chain alkyl vinyl ketones carrying spectator
aromatic rings gave rise to cyclopentenes 24 and 25 in good
yields in both cases. a-Sulfonyl esters bearing the terminal
alkynyl group also partook in the reaction to afford cyclopen-
tenes 26–29. In the case of cyclohexenone as the Michael
acceptor NMP (N-methylpyrrolidinone) was identified as a
better reaction solvent than methanol and a 5 : 1 diastereo-
meric ratio of reaction product 29 was isolated.
Pleasingly, in all of these initial experiments the dominant
reaction product was the conjugated bicyclic enone 16. Cyclo-
hexenone 11 could not be detected in any of the crude reaction
mixtures, confirming that in all cases the reactions had gone to
completion. Michael adduct 13 could not be detected in any
case, suggesting that the cyclisation stage was faster than the
Michael addition. Product isomers 14 and 15 could not be
detected in any of the crude reaction mixtures. Although
AgOTf and Au(PPh3)Cl–AgOTf were effective catalysts in the
cascade, the best result in terms of yield employed Cu(OTf)2 in
the presence of triphenylphosphine (entry 1). Accordingly,
further investigations were carried out using this catalyst–ligand
combination. Changing pyrrolidine to piperidine or n-propyla-
mine led to dramatically diminished reaction yields (entries 6
and 7) whereas employing any other typical reaction solvent in
the presence of pyrrolidine led to significantly decreased reac-
tion rates (entries 8–11). A control experiment, where pyrroli-
dine was omitted, confirmed the importance of the amine
organocatalyst in both the Michael addition and carbocyclisa-
tion steps (entry 12); although the strong base ps-BEMP12
catalysed the slow formation of 13, no bicycle 16 was observed,
thus the postulated intermediacy of an iminium ion (5 in
Scheme 1) in the Michael addition step and an enamine (7 in
Scheme 1) in the carbocyclisation step was supported.
To further investigate the scope of the reaction cascade,
arylated alkyne 30 was synthesised and tested for performance
in the reaction. Although the reaction was sluggish at room
temperature, pleasingly in methanol at 65 1C for 24 h the
desired bicyclic product 31 was formed as a single isomer in
69% yield (Scheme 3).
In the presence of excess triphenylphosphine, Cu(II) salts are
known to reduce to Cu(I) complexes such as (Ph3P)3CuX where
X is the counterion of the starting salt.13 Moreover, the ability
of Cu(I) to activate triple bonds towards nucleophilic attack has
already been demonstrated.14 Therefore we postulate that the
catalytically active metal ion species responsible for alkyne
activation in our reaction mixture is (Ph3P)3CuX (where X is
With proof of principle established and the optimal reaction
conditions identified, the scope of the cascade was surveyed by
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Notes and references
z Arylated alkyne 30 was synthesised by a Sonogashira coupling of
dimethyl propargylmalonate 12 with iodobenzene (see ESI for detailsw).
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Scheme 2 Scope of the combination catalysis cascade to cyclopentenes.
Scheme 3 Combination catalysis cascade of a non-terminal alkyne.z
6. For a similar strategy using a Michael addition reaction and a
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11. ps-BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
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either OTf or OMe). This hypothesis was supported when a
mixture of (Ph3P)3CuCl15 and AgOTf was tested for perfor-
mance in the cascade and a comparable result (3 h reaction
time, 80% yield) with respect to the Cu(OTf)2–PPh3 system was
obtained. Furthermore, 31P NMR experiments of reaction
systems using Cu(OTf)2–PPh3 or (CuOTf)2ꢁC6H6–PPh3 identi-
fied complexes common to both (see ESI for detailsw).
In summary, a mutually compatible combination of pyrro-
lidine and Cu(OTf)2–PPh3 catalysts has been identified that
promotes a new carboannulation to cyclopentene products
from a,b-unsaturated ketones and propargylated carbon
acids. Initiated through a Michael addition to the iminium
ion activated enone, the enamine intermediate is poised to
undergo C–C bond formation with the copper(I) activated
alkyne. Subsequent protonolysis, hydrolysis and isomerisation
provide the cyclopentene products in moderate to good yields.
Further studies to widen the range of substrates amenable to
this type of catalysis cascade are under investigation and the
results will be reported in due course.
We thank the European Commission (Marie Curie IEF to
AF), Universities UK, the University of Manchester, and
AstraZeneca (studentship to TY) for support.
15. W. T. Reichie, Inorg. Chim. Acta, 1971, 5, 325.
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