Generating complexity from simplicity: Pd-catalyzed or cu-promoted domino alkyne homocoupling/double [2+2] allenyne cycloaddition

Article abstract of DOI:10.1002/chem.200901574

An efficient Pd-catalyzed or Cu-promoted preparation of attached-ring bis(heterocyclic) fused cyclobutenes in a totally controlled fashion using alkyne homocoupling, as well as a double cyclization of the resulting bis (allenyne) in a domino sequence has

Full text of DOI:10.1002/chem.200901574

COMMUNICATION
DOI: 10.1002/chem.200901574
Generating Complexity from Simplicity: Pd-Catalyzed or Cu-Promoted
Domino Alkyne HomoACTHNUTRGNEUcGN oupling/Double [2+2] Allenyne Cycloaddition
Benito Alcaide,*[a] Pedro Almendros,*[b] and Cristina Aragoncillo[a]
The allene moiety has developed from almost a rarity to
an established member of the weaponry utilized in modern
organic synthetic chemistry.[1] In particular, [2+2] cycloaddi-
tion reactions of allenes with alkynes have attracted recent
attention.[2] However, stereo- and positional selectivity prob-
lems are significant. Although much effort has been devoted
to these fields, [2+2] cycloaddition of bis(allenynes) has
rarely been mentioned; only Cook et al. have reported the
formation of a monocyclized [5.4] system.[3] The main cause
of this lack might be attributed to both the difficulty of pre-
paring the starting diyne-diallenes as well as to additional
chemo- and regioselectivity problems. In a continuation of
our interest in allene chemistry,[4] we present the first exam-
ples of a double [2+2] cycloaddition in allenynes. The re-
sults of our investigation to prepare attached-ring bis(heter-
ocyclic) fused cyclobutenes using alkyne homocoupling as
pected dimeric bis(3-oxabicycloACTHUGNETRNNU[G 4.2.0]octadiene) 2a was ob-
tained in good yield by adopting a modified oxidative acety-
lenic coupling using a Pd–Cu bimetallic catalytic system and
(diacetoxyiodo)benzene (Scheme 1). These results could be
Scheme 1. Synthesis of attached-ring bis(dihydropyran-fused cyclobu-
tenes) 2a–d. Reagents and conditions: i) 2 mol% PdCl2, 2 mol% CuI,
Et3N, 6 mol% PPh3, DIB, THF, RT. THF=Tetrahydrofuran; DIB=(Di-
acetoxyiodo)benzene.
well as double cyclization of the resulting bis
domino sequence are described herein.
ACHTUNGTREN(NUNG allenyne) in a
Allenyne 1a was chosen as a model substrate for alkyne
homocoupling.[5] To screen the reactivity of the allenyne
moiety, the dimerization was studied by using 1a in the pres-
ence of a copper catalyst. The starting allenyne was recov-
ered, together with a complicated mixture of side products
when Glaser, Eglinton, or Hay protocols were applied.[6] By
contrast, difficulties were surmounted when Pd-catalyzed
oxidative homocoupling of alkynes with a stoichiometric
amount of oxidant were applied. To our delight, the unex-
explained through an unprecedented Pd–Cu bimetallic cata-
lyzed domino alkyne homocoupling/ACTHNUTRGNEUNG[2+2] allenyne bis(cy-
cloaddition). Interestingly, total regioselectivity towards
both external allenic double bonds was observed. Similar
behavior was observed for alicyclic allenynes 1b–d, provid-
ing tetracycles 2b–d in reasonable yields (Scheme 1).[7] How-
ever, variations in concentrations considerably altered re-
sults. If the reaction was performed at a lower concentration
of 0.33 molLꢀ1, the conversion dropped dramatically, and in
most cases the reaction failed completely; not even a homo-
dimerization of the alkyne moiety was detected. Dimers 2
are acid-sensitive, making the storage in a CDCl3 solution
impractical because the acid present in the deuterated sol-
vent induces ring opening and polymerization.
[a] Prof. Dr. B. Alcaide, Dr. C. Aragoncillo
Departamento de Quꢀmica Orgꢁnica I, Facultad de Quꢀmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax : (+34)91-3944103
E-mail: alcaideb@quim.ucm.es
To assess the scope, the even more challenging enantio-
pure 2-azetidinone-tethered allenynes 3 were tested as bis-
(cyclization) substrates. The starting allenynes 3a–d were
readily obtained beginning from the appropriate 4-oxoazeti-
dine-2-carbaldehyde via a regiocontrolled indium-mediated
Barbier-type carbonyl-allenylation reaction.[8] Initial at-
tempts, by employing the above Pd–Cu bimetallic catalytic
[b] Dr. P. Almendros
Instituto de Qfflmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901574.
Chem. Eur. J. 2009, 15, 9987 – 9989
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9987

system failed to give the desired product even when the re-
action temperature was raised to 808C. Different additives
and metal sources were screened with compound 3a as test
substrate. Using modified classical copper promoted condi-
tions, however, we were pleased to find that the homodimer-
preference. Substrates 1a–d and 3a–d had aryl groups at the
inside position of the allene. Unfortunately, when related al-
lenynes 1 and 3 not bearing aryl groups (R2 =Me or R2 =H)
were used, the reaction stopped at the alkyne homocoupling
step.
ization/
[2+2] bis(cyclization) sequence proceeded smoothly
Dimers 2a–d arising from racemic monomers 1a–d
appear to be diastereomeric mixtures as seem to suggest the
13C NMR data. NMR data of compounds 2 and 4 suggested
a fused cyclic structure. However, no signal for alkenyl cy-
clobutene protons was detected, indicating that substitution
occurred at the former terminal acetylenic end. The ob-
served masses from the mass spectra correspond to twice
the mass of the starting compounds, thus revealing the di-
meric nature of these polycycles. In addition, the simplicity
of the proton and carbon NMR spectra point to the C2-sym-
metrical dimmer nature of adducts 2 and 4. Such dimeric
polycycles could be formed either from a metal-promoted
[2+2] allenyne mono(cyclization) followed by dimerization
of the so-formed cyclobutene derivative or from a metal-
promoted [2+2] allenyne bis(cyclization) after homodimeri-
zation of the starting allenyne. The first hypothesis could be
safely ruled out because we were able to isolate small
amounts of diallenynyl diazetidinones of type 7 by the
above-mentioned copper-promoted conditions at short reac-
tion times. A tentative mechanistic proposal for the metal-
to afford the desired product 4a. Copper(II) acetate with
potassium carbonate was the best combination. The process
was highly solvent dependent, and the best results were ob-
tained in acetonitrile. However, reaction times for complete
conversion were considerably longer than with allenynes 1
(10 h for allenyne 1a and 72 h for allenyne 3a). At short re-
action times at room temperature, the bisACTHNUGRTENUNG(b-lactam)-1,3-
diyne homodimer was detected in appreciable amounts. Ac-
cordingly, hot solutions of allenynes 3 were exposed to the
above disclosed conditions and efficiently afforded bis(cy-
cloadduct) 4a after 2 h. Taking into account the repeatabili-
ty, the reproducibility, and the reliability of the copper-pro-
moted conditions, the modified Eglinton protocol was se-
lected as the method of choice.[9] In this way, enantiopure at-
tached-ring bis(tricyclic) b-lactams 4a–d were conveniently
prepared in good overall yields by domino alkyne homocou-
pling/double [2+2] bisACHTUNRGTNE(NUG allenyne) cycloaddition (Scheme 2).
promoted alkyne homocoupling/ACTHNUGRTNEUNG[2+2] allenyne bis(cycload-
dition) of allenynes is depicted in Scheme 3. It may involve
the formation of dialkynylpalladium complexes of type 5 or
copper(I) acetylides of type 6, which are then transformed
to the corresponding diynes 7.[14] For the double [2+2] alle-
nyne cyclization, it is believed that initially the metal salt re-
gioselectively forms a p complex with both the triple bond
and a double bond of substrates 6. Such p complexes may
ꢀ
undergo migratory C C coupling to give pallada- or cupra-
cyclopentenes of type 8. Following this step, intermediates 8
Scheme 2. Synthesis of enantiopure attached-ring bis(tricyclic) b-lactams
4a–d. Reagents and conditions: i) Cu
1108C. PMP=4-MeOC6H4.
A
Interestingly, the exposure of
allenynes 1a–d to the copper-
promoted
conditions
of
Scheme 2 afforded bis(hydro-
pyran-fused cyclobutenes) 2a–d
in similar yields. Compounds 4
are remarkable since they bear
a challenging dimeric tricyclic
2-azetidinone structure having
both a strained cyclobutene as
well as
a
seven-membered
ring.[10–13] No loss of stereo-
chemical integrity at the stereo-
genic centers under the domino
conditions was detected. Be-
sides, the depicted distal cyclo-
adducts were the only isomers
isolated, showing allenynes 1
Scheme 3. Mechanistic explanation for the metal-promoted alkyne homocoupling/ACHTNUGTRNEUNG[2+2] allenyne bis(cycloaddi-
and 3 the same regiochemical tion) of allenynes 1 and 3.
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Chem. Eur. J. 2009, 15, 9987 – 9989

Domino Alkyne Homocoupling/Double [2+2] Allenyne Cycloaddition
COMMUNICATION
caide, P. Almendros, T. Martꢀnez del Campo, Angew. Chem. 2007,
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would undergo rapid reductive elimination to give bis(cyclo-
butenes) 2 and 4 as the final products.[15] The observed high
regioselectivity of the reaction could be explained in terms
of the regioselective formation of metallacycles of type 8,
which would be controlled by the stereoelectronic effects of
the aryl substituent (R2) in allenynes 1 and 3. Cyclization to-
wards the internal allenic double bonds is probably restrict-
ed by the steric hindrance between the metal ligand moiety
and the aryl substituent at the putative quaternary stereo-
center.
[5] Allenynes 1a–d were prepared from the corresponding a-allenols by
treatment with propargyl bromide under phase-transfer conditions
(see the Supporting Information for details). The starting a-allenols
required for our study were prepared from the corresponding alde-
hydes as previously described: M. B. Isaac, T.-H. Chan, J. Chem.
Soc. Chem. Commun. 1995, 1003.
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[7] Attached-ring bis(heterocyclic)fused cyclobutenes 2 possess as well
a pyran moiety, which is present in a wide variety of natural prod-
ucts and biologically relevant compounds. For reviews on pyran
rings, see: a) I. Larrosa, P. Romea, F. Urpꢀ, Tetrahedron 2008, 64,
2683; b) P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006, 2045;
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In conclusion, an efficient Pd-catalyzed or Cu-promoted
preparation of attached-ring bis(heterocyclic) fused cyclobu-
tenes in a totally controlled fashion using alkyne homocou-
pling, as well as a double [2+2] cyclization of the resulting
bisACHTUNGTRENNUNG(allenyne) in a domino sequence has been accomplished.
[8] B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Eur. J. 2002, 8,
1719.
[9] B. Alcaide, P. Almendros, R. Carrascosa, R. Rodrꢀuez-Acebes, Eur.
J. Org. Chem. 2008, 1575.
Acknowledgements
Support for this work by the DGI-MEC (CTQ2006-10292) and UCM-
BSCH (Grant GR58/08) are gratefully acknowledged. C. A. thanks the
MEC for a Ramón y Cajal grant co-financed by the European Social
Fund.
[10] Tricyclic b-lactam antibiotics which are generally referred to as tri-
nems are a new class of synthetic antibacterial agents featuring good
resistance to b-lactamases and dehydropeptidases; a) O. Kanno, I.
Kawamoto, Tetrahedron 2000, 56, 5639; b) S. Hanessian, B. Reddy,
Tetrahedron 1999, 55, 3427; c) “The Chemistry of Trinems”: C.
Ghiron, T. Rossi in Targets in Heterocyclic Systems-Chemistry and
Properties, Vol. 1 (Eds.: O. A. Attanasi, D. Spinelli), Societa Chimica
Italiana, Rome, 1997, pp. 161–186.
[11] For a report on the increased antibacterial activity of b-lactam heter-
odimers in comparison with their monomeric components, see:
D. D. Long, J. B. Aggen, B. G. Christensen, J. K. Judice, S. S. Hegde,
K. Kaniga, K. M. Krause, M. S. Linsell, E. J. Moran, J. L. Pace, J.
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[12] The importance of cyclobutane containing compounds both as
target molecules as well as useful building blocks for the construc-
tion of more complex structures, has been widely demonstrated. For
a recent selected review, see: The Chemistry of Cyclobutanes (Eds.:
Z. Rappoport, J. F. Liebman), Wiley-VCH, Weinheim, 2005.
[13] Medium-sized rings represent some of the most difficult challenges
for cyclization strategies; the combination of developing ring strain
and the requirement to restrict rotations around 7–9 flexible bonds
ensures unfavorable enthalpic and entropic contributions to DG. For
reviews, see: a) C. Galli, L. Mandolini, Eur. J. Org. Chem. 2000,
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[14] Dialkynylpalladium complexes of type 5 are transformed to diynes 7
via a reductive elimination, whereas copper(I) acetylides 6 are rap-
idly oxidized by the transfer of a single electron to copper(II). De-
composition of the resultant copper(II) acetylide and recombination
of the free radicals would give the homocoupled products 7.
[15] Under Pd-catalyzed conditions, it is necessary for the catalytic cycle
that Pd0 is reoxidized to PdII, making further reductive elimination
possible; this is achieved by the addition of DIB which does not in-
terfere with the course of the reaction.
Keywords: alkynes
· allenes · copper · cycloalkenes ·
regioselectivity
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Received: June 9, 2009
Revised: July 20, 2009
Published online: August 27, 2009
Chem. Eur. J. 2009, 15, 9987 – 9989
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9989