Synthesis of spiroheterocycles by palladium-catalyzed domino cycloisomerization/cross-coupling of α-allenols and Baylis-Hillman acetates

Article abstract of DOI:10.1002/chem.200900096

A new domino hetero-cyclization/cross-coupling reaction of α-allenols and BH acetates that includes [(2,5-dihydrofuran-3-yl)methyl]acrylate derivatives, was prepared. The domino reaction provides a facile access to functionalized spiroindolinones, which p

Full text of DOI:10.1002/chem.200900096

DOI: 10.1002/chem.200900096
Synthesis of Spiroheterocycles by Palladium-Catalyzed Domino
Cycloisomerization/Cross-Coupling of a-Allenols and Baylis–Hillman
Acetates
ACHTUNGTRENNUNG
Benito Alcaide,*[a] Pedro Almendros,*[b] Teresa Martꢀnez del Campo,[a] and
M. Teresa Quirꢁs[a]
Dedicated to Professor Josep Font on the occasion of his 70th birthday
The Baylis–Hillman (BH) reaction is a straightforward
using various palladium salts (PdCl2, [PdCl
2ACHTUNGTRENN(UNG MeCN)2], and
À
C C bond forming reaction that affords densely functional-
ized adducts, which, particularly in the form of acetyl deriva-
tives, are versatile synthetic intermediates.[1] Despite regiose-
lectivity problems, the allene moiety has developed from
almost a rarity to an established member of the weaponry
utilized in modern organic synthetic chemistry.[2] However,
although many efforts have been made in these fields, exam-
ples of the reaction between allenes and BH adducts have
not been reported yet. In continuation of our interest in het-
erocyclic and allene chemistry,[3] we now disclose the first
examples of the reaction of an allene and a BH adduct,
namely the heterocyclization cross-coupling reaction of a-al-
lenols and BH acetates.
Pd(OAc)2), solvents (N,N-dimethylformamide, acetonitrile,
ACHTUNGTRENNUNG
and dimethyl sulfoxide), and additives (alkaline carbonates
and phosphines). Disappointingly, the PdCl2-catalyzed reac-
tion of a-allenol 1a and BH acetate 2a afforded the homo-
dimer 3, which is the result of an allene oxycyclization fol-
lowed by coupling with another allene molecule rather than
with the BH adduct (Scheme 1).[5] To our delight, the above
screening revealed that PdACTHNUTRGNE(UNG OAc)2 was a competent catalyst,
Precursors for the heterocycle formation, a-allenols 1a–d,
were readily prepared in good overall yield from the corre-
sponding carbonyl compound by a regiocontrolled indium-
mediated Barbier-type carbonyl-allenylation reaction in
aqueous media using our previously described methodolo-
gy.[4] a-Allenol 1a was selected as a simple model to test the
chemical bent for the BH acetate 2a in the heterocyclization
cross-coupling sequence. The search for an effective metal
catalyst system for the tandem reaction was performed by
Scheme 1. Palladium-catalyzed reaction of a-allenol 1a with BH acetate
2a. Reagents and conditions: i) 5 mol% PdCl2, DMF, RT. ii) 5 mol%
PdACHTNUTGRNEG(UN OAc)2, K2CO3, TDMPP, DMSO, RT.
and the combination of PdACHTUNGTRENUNG(OAc)2, K2CO3, and tris(2,6-di-
methoxyphenyl)phosphine (TDMPP) in DMSO was the
most efficient system for the domino coupling. We also ex-
amined the use of PPh3 in this reaction, although the yield
of 4 (20%) was not very high in this case; this indicated that
an electron-rich phosphine was necessary. Accordingly, the
controlled reaction between a-allenol 1a and BH acetate 2a
selectively gave the [(2,5-dihydrofuran-3-yl)methyl]acrylate
4 (Scheme 1).
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. T. Martꢀnez del Campo,
Dipl.-Chem. M. T. Quirꢁs
Departamento de Quꢀmica Orgꢂnica I, Facultad de Quꢀmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax : (+34)91-3944103
Encouraged by this result, tertiary a-allenols 1b–d were
studied to determine the applicability of the tandem se-
quence for the preparation of spirocycles, which, due to
their atypical topologies, have attracted the attention of or-
ganic chemists.[6] Pleasingly, 2-indolinone-tethered allenic al-
cohol 1b underwent reaction with BH acetates 2a and 2b,
affording reasonable yields of spiroindolinones 5a and 5b
(Scheme 2).[7]
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
Instituto de Quꢀmica Orgꢂnica 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.200900096.
3344
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Chem. Eur. J. 2009, 15, 3344 – 3346

COMMUNICATION
mechanistic considerations. The total diastereoselectivity for
the spiroazetidinone 7 could be explained by invoking the
hindrance between the incoming pallada-species and the
aryl group of the BH acetate; the less sterically demanding
group (hydrogen atom) of the b-lactam ring being placed in
the same plane as the aryl group. The difference in reactivi-
ty between both types of BH acetates could be explained by
the different inductive and resonating capacities of the ester
and cyano groups. The presence of a cyano substituent in
the BH adduct probably strengthened the reactivity of the
benzylic-like carbon, thus favoring the SN1 substitution over
the SN2ꢄ substitution.
Scheme 2. Palladium-catalyzed preparation of spiroindolinones 5a and
5b. Reagents and conditions: i) 5 mol% PdACTHNUGRTNE(UNG OAc)2, K2CO3, TDMPP,
DMSO, RT.
The above domino reaction provides a facile access to
functionalized spiroindolinones, which prompted us to test it
using enantiopure 2-azetidinone-tethered allenic alcohols.
Pleasingly, a-allenols 1c and 1d reacted with BH acetates
2a and 2b to furnish selectively the desired spiroazetidi-
nones 6a–d in moderate to good yields (Scheme 3).[8,9]
The catalytic cycle proposed in Scheme 5 appears valid
for the formation of products 4–6 by the heterocyclization
cross-coupling reaction of a-allenols and BH acetates. Initial
Scheme 3. Palladium-catalyzed preparation of enantiopure spiroazetidi-
nones 6a–d. Reagents and conditions: i) 5 mol% PdACTHUNGTREN(UNGN OAc)2, K2CO3,
TDMPP, DMSO, RT. PMP=4-MeOC6H4.
When a-allenol 1c and BH acetate containing nitrile 2c
were subjected to this PdII-catalyzed protocol, the reaction
did not yield the expected adduct 6e, which would have
arisen by SN2ꢄ substitution by attack at the methylenic posi-
tion remote from the leaving group, followed by migration
of the double bond. Interestingly, under the present condi-
tions the reaction exclusively led to the spiroazetidinone 7,
probably by way of a regio- and diastereospecific SN1 substi-
tution (Scheme 4).[10] The configurational assignment at the
benzylic-like carbon atom in 7 was made taking into account
Scheme 5. Mechanistic explanation for the palladium-catalyzed oxycycli-
zation/cross-coupling reaction.
palladium(II) coordination to the 1,2-diene moiety of the a-
allenol component 1 gives an allenepalladium complex 8,
which undergoes regiocontrolled intramolecular oxypallada-
tion leading to a palladadihydrofuran intermediate 9, which,
in turn, undergoes a cross-coupling reaction with the BH
acetate 2. The coupling of vinyl palladium(II) intermediates
9 with protected BH adducts 2 that leads to species 10 takes
place regioselectively at the methylenic carbon atom of 2,
remote from the acetate group. Finally, trans-b-deacetoxy-
palladation generates [(2,5-dihydrofuran-3-yl)methyl]acry-
lates 4–6 in a highly steoselective manner as single E iso-
mers with concomitant regeneration of the PdII species.
In summary, we have developed a novel domino hetero-
cyclization/cross-coupling reaction of a-allenols and BH ace-
tates that furnishes [(2,5-dihydrofuran-3-yl)methyl]acrylate
derivatives in moderate to good yields. In addition, the pres-
ent study provides the first insight into the manner in which
the allene group and BH adducts undergo reaction.
Scheme 4. Palladium-catalyzed preparation of enantiopure spiroazetidi-
none 7. Reagents and conditions: i) 5 mol% Pd
DMSO, RT. PMP=4-MeOC6H4.
ACHTUGNTRENN(NUG OAc)2, K2CO3, TDMPP,
Chem. Eur. J. 2009, 15, 3344 – 3346
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www.chemeurj.org
3345

B. Alcaide, P. Almendros et al.
C. T. White in Spirocyclic Systems: The Total Synthesis of Natural
Products, Vol. 5 (Ed.: J. ApSimon), Wiley, New York, 1983, pp. 264–
313.
Acknowledgements
This work was supported by the DGI-MEC (Project CTQ2006-10292),
Comunidad Autꢁnoma de Madrid (CCG-07-UCM/PPQ-2308), and the
Universidad Complutense de Madrid (Grant GR74/07). T. M. C. and M.
T. Q. thank the MEC for a predoctoral grant and a studentship, respec-
tively.
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Keywords: allenes
· heterocycles · palladium · spiro
compounds · synthetic methods
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Received: January 13, 2009
Published online: February 19, 2009
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Chem. Eur. J. 2009, 15, 3344 – 3346